Drug delivery system and method of manufacturing thereof

ABSTRACT

A method of modifying the surface of a medical device to release a drug in a controlled way by providing a barrier layer on the surface of one or more drug coatings. The barrier layer consists of modified drug material converted to a barrier layer by irradiation by an accelerated neutral beam derived from an accelerated gas cluster ion beam. Also medical devices formed thereby.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication No. 61/526,186, filed on Aug. 22, 2011, and incorporatedherein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This invention relates generally to drug delivery systems such as, forexample, medical devices implantable in a mammal (e.g., coronary and/orvascular stents, implantable prostheses, etc.), and more specifically toa method and system for applying drugs to the surface of medical devicesand/or for controlling the surface characteristics of such drug deliverysystems such as, for example, the drug release rate and bio-reactivity,using beam technology, preferably through the use of an acceleratedneutral gas cluster beam (GCIB) or an accelerated neutral monomer beam,wherein the accelerated neutral gas cluster beam or accelerated neutralmonomer beam is derived from an accelerated gas cluster ion beam. Suchtechnology is applied in a manner that promotes efficacious release ofthe drugs from the surface over time.

BACKGROUND OF THE INVENTION

Medical devices intended for implant into or for direct contact with thebody or bodily tissues of a mammal (including a human), as for examplemedical prostheses or surgical implants, may be fabricated from avariety of materials including various metals, metal alloys, plastic,polymer, or co-polymer materials, solid resin materials, glassymaterials and other materials as may be suitable for the application andappropriately biocompatible. As examples, certain stainless steelalloys, cobalt-chrome alloys, titanium and titanium alloys,biodegradable metals like iron and magnesium, polyethylene and otherinert plastics have been used. Such devices include for example, withoutlimitation, vascular stents, artificial joint prostheses (and componentsthereof), coronary pacemakers, etc. Implantable medical devices arefrequently employed to deliver a drug or other biologically activebeneficial agent to the tissue or organ in which it is implanted.

A coronary or vascular stent is just one example of an implantablemedical device that has been used for localized delivery of a drug orother beneficial agent. Stents may be inserted into a blood vessel,positioned at a desired location and expanded by a balloon or othermechanical expansion device. Unfortunately, the body's response to thisprocedure often includes thrombosis or blood clotting and the formationof scar tissue or other trauma-induced tissue reactions at the treatmentsite. Statistics show that restenosis or re-narrowing of the artery byscar tissue after stent implantation occurs in a substantial percent ofthe treated patients within only six months after these procedures,leading to severe complications in many patients.

Coronary restenotic complications associated with stents are believed tobe caused by many factors acting alone or in combination. Thesecomplications can be reduced by several types of drugs introducedlocally at the site of stent implantation. Because of the substantialfinancial costs associated with treating the complications ofrestenosis, such as catheterization, re-stenting, intensive care, etc.,a reduction in restenosis rates would save money and reduce patientsuffering.

There are many current popular designs of coronary and vascular stents.Although the use of coronary stents is growing, the benefits of theiruse remain controversial in certain clinical situations or indicationsdue to their potential complications. It is widely held that during theprocess of expanding the stent, damage occurs to the endothelial liningof the blood vessel triggering a healing response that re-occludes theartery. To help combat that phenomenon, drug-bearing stents have beenintroduced to the market to reduce the incidence of restenosis orre-occluding of the blood vessel. These drugs are typically applied tothe stent surface or mixed with a liquid polymer or co-polymer that isapplied to the stent surface and subsequently hardens. When implanted,the drug elutes out of the polymeric mixture in time, releasing themedicine into the surrounding tissue. There remain a number of problemsassociated with this technology. Because the stent is expanded at thediseased site, the polymeric material has a tendency to crack andsometimes delaminate from the stent surface. These polymeric flakes cantravel throughout the cardio-vascular system and cause significantdamage. There is evidence to suggest that the polymers themselves causea toxic reaction in the body. Additionally, because of the thickness ofthe coating necessary to carry the required amount of medicine, thestents can become somewhat rigid making expansion difficult. Also,because of the volume of polymer required to adequately contain themedicine, the total amount of medicine that can be loaded may beundesirably reduced.

In other prior art stents, the bare wire or metal mesh of the stentitself is coated with one or more drugs through processes such as highpressure loading, spraying, and dipping. However, loading, spraying anddipping do not always yield the optimal, time-release dosage of thedrugs delivered to the surrounding tissue. The drug or drug/polymercoating can include several layers such as the above drug-containinglayer as well as a drug-free encapsulating layer, which can help toreduce the initial drug release amount caused by initial exposure toliquids when the device is first implanted.

A variety of methods have been employed to attach drugs or othertherapeutic agents to an implantable medical device and to control therelease rate of the drug/agent after surgical implantation. Barrierlayers of polymers or co-polymers are added on top of the drugs tocontrol the release rates of the attached drugs/agents and/or to controlthe rate of diffusion of external fluids (such as water or biologicalfluids) into the attached drugs. Drug/polymer mixtures are also employedin coating implantable medical devices. However, as previouslyexplained, these polymers or co-polymers, while contributing to thecontrol of the drug release rate, can have undesirable characteristicsthat reduce the overall medical success of the drug loaded implantabledevice and it is desirable that they could be completely eliminated.

Gas cluster ion beams have been employed to smooth or otherwise modifythe surfaces of implantable medical devices such as stents and otherimplantable medical devices. For example, U.S. Pat. No. 6,676,989C1issued to Kirkpatrick et al. teaches a GCIB processing system having aholder and manipulator suited for processing tubular or cylindricalworkpieces such as vascular stents. In another example, U.S. Pat. No.6,491,800B2 issued to Kirkpatrick et al. teaches a GCIB processingsystem having workpiece holders and manipulators for processing othertypes of non-planar medical devices, including for example, hip jointprostheses. In still another example, U.S. Pat. No. 7,105,199B2 issuedto Blinn et al. teaches the use of GCIB processing to improve theadhesion of drug coatings on stents and to modify the elution or releaserate of the drug from the coatings. Ions have long been favored for manyprocesses because their electric charge facilitates their manipulationby electrostatic and magnetic fields. This introduces great flexibilityin processing. However, in some applications, the charge that isinherent to any ion (including gas cluster ions in a GCIB) may produceundesirable effects in the processed surfaces. GCIB has a distinctadvantage over conventional ion beams in that a gas cluster ion with asingle or small multiple charge enables the transport and control of amuch larger mass-flow (a cluster may consist of hundreds or thousands ofmolecules) compared to a conventional ion (a single atom, molecule, ormolecular fragment.) Particularly in the case of electrically insulatingmaterials and materials having high electrical resistivity, such as thesurfaces of many drug coatings or many polymers, or many drug-polymermixtures, surfaces processed using ions often suffer from charge-induceddamage resulting from abrupt discharge of accumulated charges, orproduction of damaging electrical field-induced stress in the material(again resulting from accumulated charges). In many such cases, GCIBshave an advantage due to their relatively low charge per mass, but insome instances may not eliminate the target-charging problem.Furthermore, moderate to high current intensity ion beams may sufferfrom a significant space charge-induced defocusing of the beam thattends to inhibit transporting a well-focused beam over long distances.Again, due to their lower charge per mass relative to conventional ionbeams, GCIBs have an advantage, but they do not fully eliminate thespace charge transport problem. Other needs/opportunities also exist asrecognized and resolved through the present invention. In the field ofdrug-eluting medical implants, GCIB processing has been successful intreating surfaces of drug coatings on medical implants to bind thecoating to a substrate or to modify the rate at which drugs are elutedfrom the coating following implantation into a patient. However, it hasbeen noted that in some cases where GCIB has been used to process drugcoatings (which are often very thin and may comprise very expensivedrugs), there may occur a weight loss of the drug coating (indicative ofdrug loss or removal) as a result of the GCIB processing. For theparticular cases where such loss occurs (certain drugs and using certainprocessing parameters) the occurrence is generally undesirable andhaving a process with the ability to avoid the weight loss, while stillobtaining satisfactory control of the drug elution rate, is preferable.Since many drugs are electrically insulating materials, dielectricmaterials, or high electrical resistivity materials, they may besusceptible to damage by electrical charge. Such potential for damagemay be reduced when accelerated Neutral Beams are used in place of gascluster ion beams.

A further instance of need or opportunity arises from the fact thatalthough the use of beams of neutral molecules or atoms provides benefitin some surface processing applications and in space charge-free beamtransport, it has not generally been easy and economical to produceintense beams of neutral molecules or atoms except for the case ofnozzle jets, where the energies are generally on the order of a fewmilli-electron-volts per atom or molecule, and thus have limitedprocessing capabilities. More energetic neutral particles can bebeneficial or necessary in many applications, for example when it isdesirable to break surface or shallow subsurface bonds to facilitatecleaning, etching, smoothing, deposition, amorphization, or to producesurface chemistry effects. In such cases, energies of from about an eVup to a few thousands of eV per particle can often be useful. Methodsand apparatus for forming such Neutral Beams by first forming anaccelerated charged GCIB and then neutralizing or arranging forneutralization of at least a fraction of the beam and separating thecharged and uncharged fractions are disclosed herein. The Neutral Beamsmay consist of neutral gas clusters, neutral monomers, or a combinationof both. Although GCIB processing has been employed successfully formany applications, there are new and existing application needs,especially in relation to processing drug coatings for forming drugeluting medical devices, not fully met by GCIB or other state of the artmethods and apparatus, and wherein accelerated Neutral Beams may providesuperior results. For example, in many situations, while a GCIB canproduce dramatic atomic-scale smoothing of an initially somewhat roughsurface, the ultimate smoothing that can be achieved is often less thanthe required smoothness, and in other situations GCIB processing canresult in roughening moderately smooth surfaces rather than smoothingthem further.

In view of the importance of in situ drug delivery, it is desirable tohave control over the drug release rate from the implantable device aswell as control over other surface characteristics of the drug deliverymedium and to accomplish such control without damage to the drug or anyinsulating materials or high electrical resistivity materials that maybe present in the device.

It is therefore an object of this invention to provide a means ofcontrolling surface characteristics of a drug eluting material usingaccelerated Neutral Beam technology.

It is a further object of this invention to improve the functionalcharacteristics of known in situ drug release mechanisms usingaccelerated Neutral Beam technology.

Still another object of this invention is to provide a medical devicethat is a drug delivery system for delivering a quantity of a drug withtemporal control of the drug delivery by employing barrier layers formedby irradiation with an accelerated Neutral Beam.

Still another object of this invention is to provide other devices thathave coatings, wherein the release, evolution, or loss of the coatingmay be temporally controlled by employing barrier layers formed byirradiation of the coating material with an accelerated Neutral Beam.

SUMMARY OF THE INVENTION

The objects set forth above as well as further and other objects andadvantages of the present invention are achieved by the inventiondescribed herein below. The present invention is directed to the use ofNeutral Beam processing of materials (including drugs) attached tosurfaces (including surfaces of medical devices intended for surgicalimplant) to modify and delay or otherwise improve the rate at which thematerials are released from the surface (as for example by elution,evaporation, or sublimation). In the case of implantable drug coatedmedical devices, the release mechanism is normally by elution.

The present invention is directed to the use of accelerated Neutral Beamprocessing to modify the surface of drug or other coating to modify asurface layer of the drug or other coating material so as to control therate at which the drug or material is released or eluted and/or tocontrol the rate at which external fluids penetrate through the surfacelayer to the underlying drug, thereby eliminating the need for apolymer, co-polymer or any other binding agent and transforming themedical device surface into a drug delivery system. This will preventthe problem of toxicity and the damage caused by transportation ofdelaminated polymeric material throughout the body. Unlike the prior artstents that utilize a separately applied polymer barrier layer materialor a drug-polymer (or co-polymer) mixture to control drug release orelution rate, the present invention provides the ability to completelyavoid the use of a polymer or co-polymer binder or barrier layer in thepreparation of a drug-releasing implantable medical device.

Beams of energetic conventional ions, accelerated electrically chargedatoms or molecules, are widely utilized to form semiconductor devicejunctions, to modify surfaces by sputtering, and to modify theproperties of thin films. Unlike conventional ions, gas cluster ions areformed from clusters of large numbers (having a typical distribution ofseveral hundreds to several thousands with a mean value of a fewthousand) of weakly bound atoms or molecules of materials that aregaseous under conditions of standard temperature and pressure (commonlyoxygen, nitrogen, or an inert gas such as argon, for example, but anycondensable gas can be used to generate gas cluster ions) with eachcluster sharing one or more electrical charges, and which areaccelerated together through large electric potential differences (onthe order of from about 3 kV to about 70 kV or more) to have high totalenergies. After gas cluster ions have been formed and accelerated, theircharge states may be altered or become altered (even neutralized) bycollisions with other cluster ions, other neutral clusters, or residualbackground gas particles, and thus they may fragment or may be inducedto fragment into smaller cluster ions or into monomer ions and/or intoneutralized smaller clusters and neutralized monomers, but the resultingcluster ions, neutral clusters, and monomer ions and neutral monomerstend to retain the relatively high velocities and energies that resultfrom having been accelerated through large electric potentialdifferences, with the accelerated gas cluster ion energy beingdistributed over the fragments.

Because the energies of individual atoms within an energetic gas clusterion are very small, typically a few eV to some tens of eV, the atomspenetrate through only a few atomic layers, at most, of a target surfaceduring impact. This shallow penetration (typically a few nanometers toabout ten nanometers, depending on the beam acceleration) of theimpacting atoms means all of the energy carried by the entire clusterion is consequently dissipated in an extremely small volume in the topsurface layer during a time period less than a microsecond. This isdifferent from using conventional ion beams where the penetration intothe material is sometimes several hundred nanometers, producing changesdeep below the surface of the material. Because of the high total energyof the gas cluster ion and extremely small interaction volume, thedeposited energy density at the impact site is far greater than in thecase of bombardment by conventional ions. For this reason, the GCIB oran accelerated Neutral Beam derived from a GCIB is capable ofinteracting with the surface of an organic material like a drug toproduce profound changes in a very shallow surface layer of about 10nanometers of less. Such changes may include cross linking of molecules,densification of the surface layer, carbonization of organic materialsin the surface layer, polymerization, and other forms of denaturization.

As used herein, the terms “GCIB”, “gas cluster ion beam” and “gascluster ion” are intended to encompass not only ionized beams and ions,but also accelerated beams and ions that have had all or a portion oftheir charge states modified (including neutralized) following theiracceleration. The terms “GCIB” and “gas cluster ion beam” are intendedto encompass all beams that comprise accelerated gas cluster ions eventhough they may also comprise non-clustered particles. As used herein,the term “Neutral Beam” is intended to mean a beam of neutral gasclusters and/or neutral monomers derived from an accelerated gas clusterion beam and wherein the acceleration results from acceleration of a gascluster ion beam. As used herein, the term “monomer” refers equally toeither a single atom or a single molecule. The terms “atom,” “molecule,”and “monomer” may be used interchangeably and all refer to theappropriate monomer that is characteristic of the gas under discussion(either a component of a cluster, a component of a cluster ion, or anatom or molecule). For example, a monatomic gas like argon may bereferred to in terms of atoms, molecules, or monomers and each of thoseterms means a single atom. Likewise, in the case of a diatomic gas likenitrogen, it may be referred to in terms of atoms, molecules, ormonomers, each term meaning a diatomic molecule. Furthermore a moleculargas like CO2, may be referred to in terms of atoms, molecules, ormonomers, each term meaning a three atom molecule, and so forth. Theseconventions are used to simplify generic discussions of gases and gasclusters or gas cluster ions independent of whether they are monatomic,diatomic, or molecular in their gaseous form.

As used herein, the term “drug” is intended to mean a therapeutic agentor a material that is active in a generally beneficial way, which can bereleased or eluted locally in the vicinity of an implantable medicaldevice to facilitate implanting (for example, without limitation, byproviding lubrication) the device, or to facilitate (for example,without limitation, through biological or biochemical activity) afavorable medical or physiological outcome of the implantation of thedevice. “Drug” is not intended to mean a mixture of a drug with apolymer that is employed for the purpose of binding or providingcoherence to the drug, attaching the drug to the medical device, or forforming a barrier layer to control release or elution of the drug. Adrug that has been modified by beam irradiation to densify, carbonize orpartially carbonize, partially denature, cross-link or partiallycross-link, or to at least partially polymerize molecules of the drug isintended to be included in the “drug” definition. As used herein, theterm “polymer” is intended to include co-polymers and to mean a materialthat is significantly polymerized and which is not biologically activein a generally beneficial way in either its monomer or polymer form.Typical polymers may include, without limitation, polylactic acid,polyglycolic acid, polylactic-co-glycolic acid, polylacticacid-co-caprolactone, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyorthoesters, polysaccharides, polysaccharidederivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan,various celluloses, polypeptides, polylysine, polyglutamic acid,polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate,polyhydroxy butyrate, and polyphosphate esters. The term “polymer” isnot intended to include a drug that has been modified by beamirradiation to densify, carbonize or partially carbonize, partiallydenature, cross-link or partially cross-link, or to at least partiallypolymerize molecules of the drug.

As used herein, the term “elution” is intended to mean the release of anat least somewhat soluble drug material from a drug source on a medicaldevice or in a hole in a medical device by gradual solution of the drugin a solvent, typically a bodily fluid solvent encountered afterimplantation of the medical device in a subject. In many cases thesolubility of a drug material is high enough that the release of thedrug into solution occurs more rapidly than desired, undesirablyshortening the therapeutic lifetime of the drug following implantationof the medical device. The rate of elution or rate of release of thedrug may depend on many factors such as for examples, solubility of thedrug or exposed surface area between the drug and the solvent or mixtureof the drug with other materials to reduce solubility. However, barrieror encapsulating layers between the drug and solvent can also modify therate of elution or release of the drug. It is often desirable to delaythe rate of release by elution to extend the time of therapeuticinfluence at the implant site. The desired elution rates are well knownper se to those working in the arts of the medical devices. The presentinvention enhances their control of those rates in the devices. See,e.g. http://www.news-medical.net/health/Drug-Eluting-Stent-Design.aspx(duration of elution). U.S. Pat. No. 3,641,237 teaches some specificdrug elution rates. Haery et al., “Drug-eluting stents: The beginning ofthe end of restenosis?”, Cleveland Clinic Journal of Medicine, V71(10),(2004), includes some details of drug release rates for stents at pg.818, Col. 2, paragraph 5. As used herein, the term “diffusion” isintended to mean the concentration gradient driven transport of amaterial across or through a barrier layer. A fluid (such as abiological fluid) diffusing across a barrier layer typically results ina molecular scale movement from the side on which the fluid is moreabundant to the side where it is less abundant, with a resultingconcentration gradient within the layer.

When accelerated gas cluster ions are fully dissociated and neutralized,the resulting neutral monomers will have energies approximately equal tothe total energy of the original accelerated gas cluster ion, divided bythe number, NI, of monomers that comprised the original gas cluster ionat the time it was accelerated. Such dissociated neutral monomers willhave energies on the order of from about 1 eV to tens or even as much asa few thousands of eV, depending on the original accelerated energy ofthe gas cluster ion and the size of the gas cluster at the time ofacceleration.

Gas cluster ion beams are generated and transported for purposes ofirradiating a workpiece according to known techniques. Various types ofholders are known in the art for holding the object in the path of theGCIB for irradiation and for manipulating the object to permitirradiation of a multiplicity of portions of the object. Neutral Beamsmay be generated and transported for purposes of irradiating a workpieceaccording to techniques taught herein.

The present invention may employ a high beam purity method and systemfor deriving from an accelerated gas cluster ion beam an acceleratedneutral gas cluster and/or preferably monomer beam that can be employedfor a variety of types of surface and shallow subsurface materialsprocessing and which is capable, for many applications, of superiorperformance compared to conventional GCIB processing. It can providewell-focused, accelerated, intense neutral monomer beams with particleshaving energies in the range of from about 1 eV to as much as a fewthousand eV. This is an energy range in which it has heretofore beenimpractical with simple, relatively inexpensive apparatus to formintense neutral beams.

These accelerated Neutral Beams are generated by first forming aconventional accelerated GCIB, then partly or essentially fullydissociating it by methods and operating conditions that do notintroduce impurities into the beam, then separating the remainingcharged portions of the beam from the neutral portion, and subsequentlyusing the resulting accelerated Neutral Beam for workpiece processing.Depending on the degree of dissociation of the gas cluster ions, theNeutral Beam produced may be a mixture of neutral gas monomers and gasclusters or may essentially consist entirely or almost entirely ofneutral gas monomers. It is preferred that the accelerated Neutral Beamis a fully dissociated neutral monomer beam.

An advantage of the Neutral Beams that may be produced by the methodsand apparatus of this invention, is that they may be used to processelectrically insulating materials without producing damage to thematerial due to charging of the surfaces of such materials by beamtransported charges as commonly occurs for all ionized beams includingGCIB. For example, in semiconductor and other electronic applications,ions often contribute to damaging or destructive charging of thindielectric films such as oxides, nitrides, etc. The use of Neutral Beamscan enable successful beam processing of polymer, dielectric, and/orother electrically insulating or high electrical resistivity materials,coatings, and films in other applications where ion beams may produceundesired side effects due to surface or other charging effects.Examples include (without limitation) processing of corrosion inhibitingcoatings, and irradiation cross-linking and/or polymerization of organicfilms. In other examples, Neutral Beam induced modifications of polymeror other dielectric materials (e.g. sterilization, smoothing, improvingsurface biocompatibility, and improving attachment of and/or control ofelution rates of drugs) may enable the use of such materials in medicaldevices for implant and/or other medical/surgical applications. Furtherexamples include Neutral Beam processing of glass, polymer, and ceramicbio-culture labware and/or environmental sampling surfaces where suchbeams may be used to improve surface characteristics like, for example,roughness, smoothness, hydrophilicity, and biocompatibility.

Since the parent GCIB, from which accelerated Neutral Beams may beformed by the methods and apparatus of the invention, comprises ions itis readily accelerated to desired energy and is readily focused usingconventional ion beam techniques. Upon subsequent dissociation andseparation of the charged ions from the neutral particles, the neutralbeam particles tend to retain their focused trajectories and may betransported for extensive distances with good effect.

When neutral gas clusters in a jet are ionized by electron bombardment,they become heated and/or excited. This may result in subsequentevaporation of monomers from the ionized gas cluster, afteracceleration, as it travels down the beamline. Additionally, collisionsof gas cluster ions with background gas molecules in the ionizer,accelerator and beamline regions, also heat and excite the gas clusterions and may result in additional subsequent evolution of monomers fromthe gas cluster ions following acceleration. When these mechanisms forevolution of monomers are induced by electron bombardment and/orcollision with background gas molecules (and/or other gas clusters) ofthe same gas from which the GCIB was formed, no contamination iscontributed to the beam by the dissociation processes that results inevolving the monomers.

There are other mechanisms that can be employed for dissociating (orinducing evolution of monomers from) gas cluster ions in a GCIB withoutintroducing contamination into the beam. Some of these mechanisms mayalso be employed to dissociate neutral gas clusters in a neutral gascluster beam. One mechanism is laser irradiation of the cluster-ion beamusing infra-red or other laser energy. Laser-induced heating of the gascluster ions in the laser irradiated GCIB results in excitement and/orheating of the gas cluster ions and causes subsequent evolution ofmonomers from the beam. Another mechanism is passing the beam through athermally heated tube so that radiant thermal energy photons impact thegas cluster ions in the beam. The induced heating of the gas clusterions by the radiant thermal energy in the tube results in excitementand/or heating of the gas cluster ions and causes subsequent evolutionof monomers from the beam. In another mechanism, crossing the gascluster ion beam by a gas jet of the same gas or mixture as the sourcegas used in formation of the GCIB (or other non-contaminating gas)results in collisions of monomers of the gas in the gas jet with the gasclusters in the ion beam producing excitement and/or heating of the gascluster ions in the beam and subsequent evolution of monomers from theexcited gas cluster ions. By depending entirely on electron bombardmentduring initial ionization and/or collisions (with other cluster ions, orwith background gas molecules of the same gas(es) as those used to formthe GCIB) within the beam and/or laser or thermal radiation and/orcrossed jet collisions of non-contaminating gas to produce the GCIBdissociation and/or fragmentation, contamination of the beam bycollision with other materials is avoided.

As a neutral gas cluster jet from a nozzle travels through an ionizingregion where electrons are directed to ionize the clusters, a clustermay remain un-ionized or may acquire a charge state, q, of one or morecharges (by ejection of electrons from the cluster by an incidentelectron). The ionizer operating conditions influence the likelihoodthat a gas cluster will take on a particular charge state, with moreintense ionizer conditions resulting in greater probability that ahigher charge state will be achieved. More intense ionizer conditionsresulting in higher ionization efficiency may result from higherelectron flux and/or higher (within limits) electron energy. Once thegas cluster has been ionized, it is typically extracted from theionizer, focused into a beam, and accelerated by falling through anelectric field. The amount of acceleration of the gas cluster ion isreadily controlled by controlling the magnitude of the acceleratingelectric field. Typical commercial GCIB processing tools generallyprovide for the gas cluster ions to be accelerated by an electric fieldhaving an adjustable accelerating potential, VAcc, typically of, forexample, from about 1 kV to 70 kV (but not limited to that range—VAcc upto 200 kV or even more may be feasible). Thus a singly charged gascluster ion achieves an energy in the range of from 1 to 70 keV (or moreif larger VAcc is used) and a multiply charged (for example, withoutlimitation, charge state, q=3 electronic charges) gas cluster ionachieves an energy in the range of from 3 to 210 keV (or more for higherVAcc). For other gas cluster ion charge states and accelerationpotentials, the accelerated energy per cluster is qVAcc eV. From a givenionizer with a given ionization efficiency, gas cluster ions will have adistribution of charge states from zero (not ionized) to a higher numbersuch as for example 6 (or with high ionizer efficiency, even more), andthe most probable and mean values of the charge state distribution alsoincrease with increased ionizer efficiency (higher electron flux and/orenergy). Higher ionizer efficiency also results in increased numbers ofgas cluster ions being formed in the ionizer. In many cases, GCIBprocessing throughput increases when operating the ionizer at highefficiency results in increased GCIB current. A downside of suchoperation is that multiple charge states that may occur on intermediatesize gas cluster ions can increase crater and/or rough interfaceformation by those ions, and often such effects may operatecounterproductively to the intent of the processing. Thus for many GCIBsurface processing recipes, selection of the ionizer operatingparameters tends to involve more considerations than just maximizingbeam current. In some processes, use of a “pressure cell” (see U.S. Pat.No. 7,060,989, to Swenson et al.) may be employed to permit operating anionizer at high ionization efficiency while still obtaining acceptablebeam processing performance by moderating the beam energy by gascollisions in an elevated pressure “pressure cell.”

With the present invention there is no downside to operating the ionizerat high efficiency—in fact such operation is sometimes preferred. Whenthe ionizer is operated at high efficiency, there may be a wide range ofcharge states in the gas cluster ions produced by the ionizer. Thisresults in a wide range of velocities in the gas cluster ions in theextraction region between the ionizer and the accelerating electrode,and also in the downstream beam. This may result in an enhancedfrequency of collisions between and among gas cluster ions in the beamthat generally results in a higher degree of fragmentation of thelargest gas cluster ions. Such fragmentation may result in aredistribution of the cluster sizes in the beam, skewing it toward thesmaller cluster sizes. These cluster fragments retain energy inproportion to their new size (N) and so become less energetic whileessentially retaining the accelerated velocity of the initialunfragmented gas cluster ion. The change of energy with retention ofvelocity following collisions has been experimentally verified (as forexample reported in Toyoda, N. et al., “Cluster size dependence onenergy and velocity distributions of gas cluster ions after collisionswith residual gas,” Nucl. Instr. & Meth. in Phys. Research B 257 (2007),pp 662-665). Fragmentation may also result in redistribution of chargesin the cluster fragments. Some uncharged fragments likely result andmulti-charged gas cluster ions may fragment into several charged gascluster ions and perhaps some uncharged fragments. It is understood bythe inventors that design of the focusing fields in the ionizer and theextraction region may enhance the focusing of the smaller gas clusterions and monomer ions to increase the likelihood of collision withlarger gas cluster ions in the beam extraction region and in thedownstream beam, thus contributing to the dissociation and/orfragmenting of the gas cluster ions.

In an embodiment of the present invention, background gas pressure inthe ionizer, acceleration region, and beamline may optionally bearranged to have a higher pressure than is normally utilized for goodGCIB transmission. This can result in additional evolution of monomersfrom gas cluster ions (beyond that resulting from the heating and/orexcitement resulting from the initial gas cluster ionization event).Pressure may be arranged so that gas cluster ions have a short enoughmean-free-path and a long enough flight path between ionizer andworkpiece that they must undergo multiple collisions with background gasmolecules.

For a homogeneous gas cluster ion containing N monomers and having acharge state of q and which has been accelerated through an electricfield potential drop of VAcc volts, the cluster will have an energy ofapproximately qVAcc/NI eV per monomer, where NI is the number ofmonomers in the cluster ion at the time of acceleration. Except for thesmallest gas cluster ions, a collision of such an ion with a backgroundgas monomer of the same gas as the cluster source gas will result inadditional deposition of approximately qVAcc/NI eV into the gas clusterion. This energy is relatively small compared to the overall gas clusterion energy (qVAcc) and generally results in excitation or heating of thecluster and in subsequent evolution of monomers from the cluster. It isbelieved that such collisions of larger clusters with background gasseldom fragment the cluster but rather heats and/or excites it to resultin evolution of monomers by evaporation or similar mechanisms.Regardless of the source of the excitation that results in the evolutionof a monomer or monomers from a gas cluster ion, the evolved monomer(s)have approximately the same energy per particle, qVAcc/NI eV, and retainapproximately the same velocity and trajectory as the gas cluster ionfrom which they have evolved. When such monomer evolutions occur from agas cluster ion, whether they result from excitation or heating due tothe original ionization event, a collision, or radiant heating, thecharge has a high probability of remaining with the larger residual gascluster ion. Thus after a sequence of monomer evolutions, a large gascluster ion may be reduced to a cloud of co-traveling monomers withperhaps a smaller residual gas cluster ion (or possibly several iffragmentation has also occurred). The co-traveling monomers followingthe original beam trajectory all have approximately the same velocity asthat of the original gas cluster ion and each has energy ofapproximately qVAcc/NI eV. For small gas cluster ions, the energy ofcollision with a background gas monomer is likely to completely andviolently dissociate the small gas cluster and it is uncertain whetherin such cases the resulting monomers continue to travel with the beam orare ejected from the beam.

Prior to the GCIB reaching the workpiece, the remaining chargedparticles (gas cluster ions, particularly small and intermediate sizegas cluster ions and some charged monomers, but also including anyremaining large gas cluster ions) in the beam are separated from theneutral portion of the beam, leaving only a Neutral Beam for processingthe workpiece.

In typical operation, the fraction of power in the neutral beamcomponents relative to that in the full (charged plus neutral) beamdelivered at the processing target is in the range of from about 5% to95%, so by the separation methods and apparatus of the present inventionit is possible to deliver that portion of the kinetic energy of the fullaccelerated charged beam to the target as a Neutral Beam.

The dissociation of, the gas cluster ions and thus the production ofhigh neutral monomer beam energy is facilitated by 1) Operating athigher acceleration voltages. This increases qVAcc/N for any givencluster size. 2) Operating at high ionizer efficiency. This increasesqVAcc/N for any given cluster size by increasing q and increasescluster-ion on cluster-ion collisions in the extraction region due tothe differences in charge states between clusters; 3) Operating at ahigh ionizer, acceleration region, or beamline pressure or operatingwith a gas jet crossing the beam, or with a longer beam path, all ofwhich increase the probability of background gas collisions for a gascluster ion of any given size; 4) Operating with laser irradiation orthermal radiant heating of the beam, which directly promote evolution ofmonomers from the gas cluster ions; and 5) Operating at higher nozzlegas flow, which increases transport of gas, clustered and perhapsunclustered into the GCIB trajectory, which increases collisionsresulting in greater evolution of monomers.

Measurement of the Neutral Beam cannot be made by current measurement asis convenient for gas cluster ion beams. A Neutral Beam power sensor isused to facilitate dosimetry when irradiating a workpiece with a NeutralBeam. The Neutral Beam sensor is a thermal sensor that intercepts thebeam (or optionally a known sample of the beam). The rate of rise oftemperature of the sensor is related to the energy flux resulting fromenergetic beam irradiation of the sensor. The thermal measurements mustbe made over a limited range of temperatures of the sensor to avoiderrors due to thermal re-radiation of the energy incident on the sensor.For a GCIB process, the beam power (watts) is equal to the beam current(amps) times VAcc, the beam acceleration voltage. When a GCIB irradiatesa workpiece for a period of time (seconds), the energy (joules) receivedby the workpiece is the product of the beam power and the irradiationtime. The processing effect of such a beam when it processes an extendedarea is distributed over the area (for example, cm2). For ion beams, ithas been conveniently conventional to specify a processing dose in termsof irradiated ions/cm2, where the ions are either known or assumed tohave at the time of acceleration an average charge state, q, and to havebeen accelerated through a potential difference of, VAcc volts, so thateach ion carries an energy of q VAcc eV (an eV is approximately1.6×10-19 joule). Thus an ion beam dose for an average charge state, q,accelerated by VAcc and specified in ions/cm2 corresponds to a readilycalculated energy dose expressible in joules/cm2. For an acceleratedNeutral Beam derived from an accelerated GCIB as utilized in the presentinvention, the value of q at the time of acceleration and the value ofVAcc is the same for both of the (later-formed and separated) chargedand uncharged fractions of the beam. The power in the two (neutral andcharged) fractions of the GCIB divides proportionally to the mass ineach beam fraction. Thus for the accelerated Neutral Beam as employed inthe invention, when equal areas are irradiated for equal times, theenergy dose (joules/cm2) deposited by the Neutral Beam is necessarilyless than the energy dose deposited by the full GCIB. By using a thermalsensor to measure the power in the full GCIB PG and that in the NeutralBeam PN (which is commonly found to be about 5% to 95% that of the fullGCIB) it is possible to calculate a compensation factor for use in theNeutral Beam processing dosimetry. When PN is aPG, then the compensationfactor is, k=1/a. Thus if a workpiece is processed using a Neutral Beamderived from a GCIB, for a time duration is made to be k times greaterthan the processing duration for the full GCIB (including charged andneutral beam portions) required to achieve a dose of D ions/cm2, thenthe energy doses deposited in the workpiece by both the Neutral Beam andthe full GCIB are the same (though the results may be different due toqualitative differences in the processing effects due to differences ofparticle sizes in the two beams.) As used herein, a Neutral Beam processdose compensated in this way is sometimes described as having anenergy/cm2 equivalence of a dose of D ions/cm2.

Use of a Neutral Beam derived from a gas cluster ion beam in combinationwith a thermal power sensor for dosimetry in many cases has advantagescompared with the use of the full gas cluster ion beam or an interceptedor diverted portion, which inevitably comprises a mixture of gas clusterions and neutral gas clusters and/or neutral monomers, and which isconventionally measured for dosimetry purposes by using a beam currentmeasurement. Some advantages are as follows:

1) The dosimetry can be more precise with the Neutral Beam using athermal sensor for dosimetry because the total power of the beam ismeasured. With a GCIB employing the traditional beam current measurementfor dosimetry, only the contribution of the ionized portion of the beamis measured and employed for dosimetry. Minute-to-minute andsetup-to-setup changes to operating conditions of the GCIB apparatus mayresult in variations in the fraction of neutral monomers and neutralclusters in the GCIB. These variations can result in process variationsthat may be less controlled when the dosimetry is done by beam currentmeasurement.

2) With a Neutral Beam, any material may be processed, including highlyinsulating materials and other materials that may be damaged byelectrical charging effects, without the necessity of providing a sourceof target neutralizing electrons to prevent workpiece charging due tocharge transported to the workpiece by an ionized beam. When employedwith conventional GCIB, target neutralization to reduce charging isseldom perfect, and the neutralizing electron source itself oftenintroduces problems such as workpiece heating, contamination fromevaporation or sputtering in the electron source, etc. Since a NeutralBeam does not transport charge to the workpiece, such problems arereduced.

3) There is no necessity for an additional device such as a largeaperture high strength magnet to separate energetic monomer ions fromthe Neutral Beam. In the case of conventional GCIB the risk of energeticmonomer ions (and other small cluster ions) being transported to theworkpiece, where they penetrate producing deep damage, is significantand an expensive magnetic filter is routinely required to separate suchparticles from the beam. In the case of the Neutral Beam apparatus ofthe invention, the separation of all ions from the beam to produce theNeutral Beam inherently removes all monomer ions.

The application of the drug(s) to the medical device may be accomplishedby several methods. The surface of the medical device, which may becomposed, for example, of a metal, metal alloy, ceramic, or many othermaterials, is first processed to form one or more holes in the surfacethereof. The desired drug(s) is then deposited into the holes. The drugdeposition may be by any of numerous methods, including spraying,dipping, electrostatic deposition, ultrasonic spraying, vapordeposition, or by discrete droplet-on-demand fluid jetting technology.When spraying, dipping, electrostatic deposition, ultrasonic spraying,vapor deposition, or similar techniques are employed, a conventionalmasking scheme may be employed to limit deposition to selectedlocations. Discrete droplet-on-demand fluid-jetting is a preferredmethod because it provides the ability to introduce precise volumes ofliquid drugs or drugs-in-solution into precisely programmable locations.Discrete droplet-on-demand fluid jetting may be accomplished usingcommercially available fluid-jet print head jetting devices as areavailable (for example, not limitation) from MicroFab Technologies,Inc., of Plano, Tex.

After the devices have been drug-loaded, the present invention usesaccelerated Neutral Beam irradiation, to modify a very shallow surfacelayer of the retained drug to alter the drug in that layer in a way thatmodifies its properties in a way that forms a thin surface film withbarrier properties that limit diffusion across the surface film. Thisresults in the ability to control the rate of diffusion of water orother biological fluids into the drug retained in the hole, and tocontrol the rate of elution of the drug out from the hole. Themodification of the surface portion of the drug that becomes the surfacefilm having barrier properties may consist of any of severalmodification outcomes, depending on the nature of the drug and theparameters of the accelerated Neutral Beam processing. Possible outcomesinclude cross-linking or polymerizing of the drug molecules,carbonization of the drug material by driving out more volatile atomsfrom the molecules, densification of the drug, and other forms ofdenaturization that result in reduced solubility, erodibility, and/or inreduced porosity or diffusion rates.

In addition to simple coating of medical devices with drugs, in somesituations, stents and other medical devices utilize cavities (holes) tocontain larger quantities of drugs. In such cases barrier layers formedon the surfaces of the contained drugs also benefit from formation byirradiation with accelerated Neutral Beam irradiation, and eliminate theneed (and possible adverse side effects) of adding additional materialssuch as polymer caps or barrier layers to retain the drugs and modify ordelay elution characteristics. In exemplary embodiments described hereinwhere the use of holes is described for retaining drugs, it should beunderstood, that the same principles of barrier layer formation usingaccelerated Neutral Beams are equally applicable to simple coatings onflat surfaces.

One embodiment of the present invention provides a medical device havinga surface adapted for delivering one or more drugs, comprising: and oneor more drug coating layers on the surface of the device, at least oneof the drug coating layers having at least one barrier layer adapted forcontrolling a rate of flow of material across the at least one barrierlayer, and further wherein the at least one barrier layer consists ofdrug modified by Neutral Beam irradiation. The at least one barrierlayer may control a release rate of drugs; control an elution rate ofdrugs; or control an inward diffusion rate of a fluid into at least oneof the one or more drug coating layers.

At least one drug coating layer of the one or more drug coating layersmay contain a first quantity of a first drug, the first drug overlaid bya first barrier layer comprising modified first drug, the first barrierlayer overlaid by a second quantity of a second drug, the second drugoverlaid by a second barrier layer comprising modified second drug. Thefirst drug and the second drug may be the same drug or different drugs;and the first barrier layer and the second barrier layer may beconstructed to control a temporal release profile of the first andsecond drugs. The controlled flow rate may be: a drug elution rate; adrug release rate; or a fluid diffusion rate. The medical device may beany of: a vascular stent; a coronary stent; an artificial jointprosthesis; an artificial joint prosthesis component; or a coronarypacemaker. The at least one barrier layer may comprise modified drug isselected from the group consisting of: cross-linked drug molecules; adensified drug; a carbonized organic drug material; a polymerized drug;or a denaturized drug; and combinations thereof. The at least onebarrier layer may comprise a biologically active material.

Another embodiment of the present invention provides a method ofmodifying a surface of a medical device comprising the steps: a.depositing a first drug coating layer on at least a portion of thesurface of the medical device; b. optionally depositing one or moreadditional drug coating layers on the first drug coating layer to form aplurality of drug coating layers; c. forming an accelerated NeutralBeam; and d. irradiating a first exposed surface of at least one of thefirst drug coating layer or any additional drug coating layer with theNeutral Beam to form a barrier layer at the first exposed surface.

The method may further comprise the steps, prior to the depositing stepa.: forming a second beam; and second irradiating at least a portion ofthe surface of the medical device with the second beam to: clean the atleast a portion of the surface of the medical device; smooth the atleast a portion of the surface of the medical device; or remove a sharpor burred edge on the at least a portion of the surface of the medicaldevice. The irradiating step d. may form the barrier layer by modifyingthe drug at the exposed surface by: cross-linking molecules of the drug;densifying the drug; carbonizing the drug; polymerizing the drug; ordenaturing the drug. The barrier layer may control a rate of inwarddiffusion of a fluid into the drug coating. The barrier layer maycontrol a rate of outward elution of drug from the drug coating. TheNeutral Beam may be derived from an accelerated gas cluster ion beam. Afirst drug coating layer and an additional drug coating layer maycomprise different drug materials.

The method may comprise the additional steps forming a third beam andirradiating a second exposed surface of at least one of the first drugcoating layer or any additional drug coating layer with the third beamto form a second barrier layer at the second exposed surface. The thirdbeam may be a Neutral Beam. The third beam may be a gas cluster ionbeam. The first barrier layer and the second barrier layer may havedifferent properties for differently controlling elution rates of twodrug coating layers.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention, together with otherand further objects thereof, reference is made to the accompanyingdrawings, wherein:

FIG. 1A is a coronary stent with through-holes as may be employed inembodiments of the invention. FIG. 1B is a second view of the coronarystent simplified for clarity by removal of detail beyond the nearestsurface;

FIG. 2 is a view of coronary stent with blind-holes as may be employedin embodiments of the invention;

FIG. 3 is an atomic force microscope image showing the surface of acoronary stent before GCIB processing;

FIG. 4 is an atomic force microscope image showing the surface of acoronary stent after GCIB processing;

FIG. 5 is a cross section of a drug delivery system prior to processingin accordance with the present invention;

FIG. 6 is a cross section of the drug delivery system of FIG. 5 shownduring gas cluster ion beam processing performed in accordance with thepresent invention;

FIG. 7 is a schematic illustrating elements of a GCIB processingapparatus 1100 for processing a workpiece using a GCIB;

FIG. 8 is a schematic illustrating elements of another GCIB processingapparatus 1200 for workpiece processing using a GCIB, wherein scanningof the ion beam and manipulation of the workpiece is employed;

FIG. 9 is a schematic of a Neutral Beam processing apparatus 1300according to an embodiment of the invention, which uses electrostaticdeflection plates to separate the charged and uncharged beams;

FIG. 10 is a schematic of a Neutral Beam processing apparatus 1400according to an embodiment of the invention, using a thermal sensor forNeutral Beam measurement;

FIGS. 11A, 11B, 11C, and 11D show processing results indicating that fora metal surface, processing by a neutral component of a beam producessuperior smoothing of the film compared to processing with either a fullGCIB or a charged component of the beam;

FIGS. 12A and 12B show comparison of a drug coating on a cobalt-chromecoupon representing a drug eluting medical device, wherein processingwith a Neutral Beam produces a superior result to processing with a fullGCIB;

FIGS. 13A, 13B, and 13C are views of prior art holes in prior artstents, illustrating various prior art loading of holes by employingpolymers;

FIGS. 14A, 14B, 14C, and 14D show steps in the formation of a drugloaded through-hole in a stent according to an embodiment of theinvention;

FIGS. 15A, 15B, and 15C show steps in the formation of a drug loadedblind-hole in a stent according to an embodiment of the invention;

FIGS. 16A and 1613 show optional steps for processing of a hole edgeaccording to an embodiment of the invention;

FIG. 17 shows a cross section view of a portion of a surface of animplantable medical device, illustrating the variety of methods that canbe employed within the present invention to control drug administration;and

FIGS. 18A, 18B, and 18C show steps in the formation of barrier films inmaterials deposited on substrates, using an embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, for simplification, item numbers fromearlier-described figures may appear in subsequently-described figureswithout discussion. Likewise, items discussed in relation to earlierfigures may appear in subsequent figures without item numbers oradditional description. In such cases items with like numbers are likeitems and have the previously-described features and functions, andillustration of items without item numbers shown in the present figurerefer to like items having the same functions as the like itemsillustrated in earlier-discussed numbered figures.

In an embodiment of the invention, a Neutral Beam derived from anaccelerated gas cluster ion beam is employed to process insulating (andother sensitive) surfaces.

Beams of energetic ions, electrically charged atoms or moleculesaccelerated through high voltages under vacuum, are widely utilized toform semiconductor device junctions, to smooth surfaces by sputtering,and to enhance the properties of semiconductor thin films. In thepresent invention, these same beams of energetic ions are utilized foraffecting surface characteristics of drug eluting medical devices, suchas, for example, coronary stents, thereby enhancing the drug deliveryproperties and the bio-compatibility of such drug delivery systems.

In the preferred embodiment of the present invention, gas cluster ionbeam GCIB processing is utilized. Gas cluster ions are formed from largenumbers of weakly bound atoms or molecules sharing common electricalcharges and accelerated together through high voltages to have hightotal energies. Cluster ions disintegrate upon impact and the totalenergy of the cluster is shared among the constituent atoms. Because ofthis energy sharing, the atoms are individually much less energetic thanthe case of conventional ions or ions not clustered together and, as aresult, the atoms penetrate to much shorter depths. Surface sputteringeffects are orders of magnitude stronger than corresponding effectsproduced by conventional ions, thereby making important micro-scalesurface effects possible that are not possible in any other way.

The concept of GCIB processing has only emerged over the past decade.Using a GCIB for dry etching, cleaning, and smoothing of materials isknown in the art and has been described, for example, by Deguchi, et al.in U.S. Pat. No. 5,814,194, “Substrate Surface Treatment Method”, 1998.Because ionized clusters containing on the order of thousands of gasatoms or molecules may be formed and accelerated to modest energies onthe order of a few thousands of electron volts, individual atoms ormolecules in the clusters may each only have an average energy on theorder of a few electron volts. It is known from the teachings of Yamadain, for example, U.S. Pat. No. 5,459,326, that such individual atoms arenot energetic enough to significantly penetrate a surface to cause theresidual sub-surface damage typically associated with plasma polishing.Nevertheless, the clusters themselves are sufficiently energetic (somethousands of electron volts) to effectively etch, smooth, or clean hardsurfaces.

Because the energies of individual atoms within a gas cluster ion arevery small, typically a few eV, the atoms penetrate through only a fewatomic layers, at most, of a target surface during impact. This shallowpenetration of the impacting atoms means all of the energy carried bythe entire cluster ion is consequently dissipated in an extremely smallvolume in the top surface layer during a period on the order of 10-12seconds (i.e. one picosecond). This is different from the case of ionimplantation, which is normally done with conventional monomer ions andwhere the intent is to penetrate into the material, sometimespenetrating several thousand angstroms, to produce changes in thesurface properties of the material. Because of the high total energy ofthe cluster ion and extremely small interaction volume, the depositedenergy density at the impact site is far greater than in the case ofbombardment by conventional monomer ions.

Reference is now made to FIG. 7, which shows a schematic configurationfor a GCIB processing apparatus 1100. A low-pressure vessel 1102 hasthree fluidly connected chambers: a nozzle chamber 1104, anionization/acceleration chamber 1106, and a processing chamber 1108. Thethree chambers are evacuated by vacuum pumps 1146 a, 1146 b, and 1146 c,respectively. A pressurized condensable source gas 1112 (for exampleargon) stored in a gas storage cylinder 1111 flows through a gasmetering valve 1113 and a feed tube 1114 into a stagnation chamber 1116.Pressure (typically a few atmospheres) in the stagnation chamber 1116results in ejection of gas into the substantially lower pressure vacuumthrough a nozzle 1110, resulting in formation of a supersonic gas jet1118. Cooling, resulting from the expansion in the jet, causes a portionof the gas jet 1118 to condense into clusters, each consisting of fromseveral to several thousand weakly bound atoms or molecules. A gasskimmer aperture 1120 is employed to control flow of gas into thedownstream chambers by partially separating gas molecules that have notcondensed into a cluster jet from the cluster jet. Excessive pressure inthe downstream chambers can be detrimental by interfering with thetransport of gas cluster ions and by interfering with management of thehigh voltages that may be employed for beam formation and transport.Suitable condensable source gases 1112 include, but are not limited toargon and other condensable noble gases, nitrogen, carbon dioxide,oxygen, and many other gases and/or gas mixtures. After formation of thegas clusters in the supersonic gas jet 1118, at least a portion of thegas clusters are ionized in an ionizer 1122 that is typically anelectron impact ionizer that produces electrons by thermal emission fromone or more incandescent filaments 1124 (or from other suitable electronsources) and accelerates and directs the electrons, enabling them tocollide with gas clusters in the gas jet 1118. Electron impacts with gasclusters eject electrons from some portion of the gas clusters, causingthose clusters to become positively ionized. Some clusters may have morethan one electron ejected and may become multiply ionized. Control ofthe number of electrons and their energies after acceleration typicallyinfluences the number of ionizations that may occur and the ratiobetween multiple and single ionizations of the gas clusters. Asuppressor electrode 1142, and grounded electrode 1144 extract thecluster ions from the ionizer exit aperture 1126, accelerate them to adesired energy (typically with acceleration potentials of from severalhundred V to several tens of kV), and focuses them to form a GCIB 1128.The region that the GCIB 1128 traverses between the ionizer exitaperture 126 and the suppressor electrode 1142 is referred to as theextraction region. The axis (determined at the nozzle 1110), of thesupersonic gas jet 1118 containing gas clusters is substantially thesame as the axis 1154 of the GCIB 1128. Filament power supply 1136provides filament voltage Vf to heat the ionizer filament 1124. Anodepower supply 1134 provides anode voltage VA to acceleratethermoelectrons emitted from filament 1124 to cause the thermoelectronsto irradiate the cluster-containing gas jet 1118 to produce clusterions. A suppression power supply 1138 supplies suppression voltage VS(on the order of several hundred to a few thousand volts) to biassuppressor electrode 1142. Accelerator power supply 1140 suppliesacceleration voltage VAcc to bias the ionizer 1122 with respect tosuppressor electrode 1142 and grounded electrode 1144 so as to result ina total GCIB acceleration potential equal to VAcc. Suppressor electrode1142 serves to extract ions from the ionizer exit aperture 1126 ofionizer 1122 and to prevent undesired electrons from entering theionizer 1122 from downstream, and to form a focused GCIB 1128.

A workpiece 1160, which may (for example) be a medical device, asemiconductor material, an optical element, or other workpiece to beprocessed by GCIB processing, is held on a workpiece holder 1162, whichdisposes the workpiece in the path of the GCIB 1128. The workpieceholder is attached to but electrically insulated from the processingchamber 1108 by an electrical insulator 1164. Thus, GCIB 1128 strikingthe workpiece 1160 and the workpiece holder 1162 flows through anelectrical lead 1168 to a dose processor 1170. A beam gate 1172 controlstransmission of the GCIB 1128 along axis 1154 to the workpiece 1160. Thebeam gate 1172 typically has an open state and a closed state that iscontrolled by a linkage 1174 that may be (for example) electrical,mechanical, or electromechanical. Dose processor 1170 controls theopen/closed state of the beam gate 1172 to manage the GCIB dose receivedby the workpiece 1160 and the workpiece holder 1162. In operation, thedose processor 1170 opens the beam gate 1172 to initiate GCIBirradiation of the workpiece 1160. Dose processor 1170 typicallyintegrates GCIB electrical current arriving at the workpiece 1160 andworkpiece holder 1162 to calculate an accumulated GCIB irradiation dose.At a predetermined dose, the dose processor 1170 closes the beam gate1172, terminating processing when the predetermined dose has beenachieved.

FIG. 8 shows a schematic illustrating elements of another GCIBprocessing apparatus 1200 for workpiece processing using a GCIB, whereinscanning of the ion beam and manipulation of the workpiece is employed.A workpiece 1160 to be processed by the GCIB processing apparatus 1200is held on a workpiece holder 1202, disposed in the path of the GCIB1128. In order to accomplish uniform processing of the workpiece 1160,the workpiece holder 1202 is designed to manipulate workpiece 1160, asmay be required for uniform processing.

Any workpiece surfaces that are non-planar, for example, spherical orcup-like, rounded, irregular, or other un-flat configuration, may beoriented within a range of angles with respect to the beam incidence toobtain optimal GCIB processing of the workpiece surfaces. The workpieceholder 1202 can be fully articulated for orienting all non-planarsurfaces to be processed in suitable alignment with the GCIB 1128 toprovide processing optimization and uniformity. More specifically, whenthe workpiece 1160 being processed is non-planar, the workpiece holder1202 may be rotated in a rotary motion 1210 and articulated inarticulation motion 1212 by an articulation/rotation mechanism 1204. Thearticulation/rotation mechanism 1204 may permit 360 degrees of devicerotation about longitudinal axis 1206 (which is coaxial with the axis1154 of the GCIB 1128) and sufficient articulation about an axis 1208perpendicular to axis 1206 to maintain the workpiece surface to within adesired range of beam incidence.

Under certain conditions, depending upon the size of the workpiece 1160,a scanning system may be desirable to produce uniform irradiation of alarge workpiece. Although often not necessary for GCIB processing, twopairs of orthogonally oriented electrostatic scan plates 1130 and 1132may be utilized to produce a raster or other scanning pattern over anextended processing area. When such beam scanning is performed, a scangenerator 1156 provides X-axis scanning signal voltages to the pair ofscan plates 1132 through lead pair 1159 and Y-axis scanning signalvoltages to the pair of scan plates 1130 through lead pair 1158. Thescanning signal voltages are commonly triangular waves of differentfrequencies that cause the GCIB 1128 to be converted into a scanned GCIB1148, which scans the entire surface of the workpiece 1160. A scannedbeam-defining aperture 1214 defines a scanned area. The scannedbeam-defining aperture 1214 is electrically conductive and iselectrically connected to the low-pressure vessel 1102 wall andsupported by support member 1220. The workpiece holder 1202 iselectrically connected via a flexible electrical lead 1222 to a faradaycup 1216 that surrounds the workpiece 1160 and the workpiece holder 1202and collects all the current passing through the defining aperture 1214.The workpiece holder 1202 is electrically isolated from thearticulation/rotation mechanism 1204 and the faraday cup 1216 iselectrically isolated from and mounted to the low-pressure vessel 1102by insulators 1218. Accordingly, all current from the scanned GCIB 1148,which passes through the scanned beam-defining aperture 1214 iscollected in the faraday cup 1216 and flows through electrical lead 1224to the dose processor 1170. In operation, the dose processor 1170 opensthe beam gate 1172 to initiate GCIB irradiation of the workpiece 1160.The dose processor 1170 typically integrates GCIB electrical currentarriving at the workpiece 1160 and workpiece holder 1202 and faraday cup1216 to calculate an accumulated GCIB irradiation dose per unit area. Ata predetermined dose, the dose processor 1170 closes the beam gate 1172,terminating processing when the predetermined dose has been achieved.During the accumulation of the predetermined dose, the workpiece 1160may be manipulated by the articulation/rotation mechanism 1204 to ensureprocessing of all desired surfaces.

FIG. 9 is a schematic of a Neutral Beam processing apparatus 1300 of anexemplary type that may be employed for Neutral Beam processingaccording to embodiments of the invention. It uses electrostaticdeflection plates to separate the charged and uncharged portions of aGCIB. A beamline chamber 1107 encloses the ionizer and acceleratorregions and the workpiece processing regions. The beamline chamber 1107has high conductance and so the pressure is substantially uniformthroughout. A vacuum pump 1146 b evacuates the beamline chamber 1107.Gas flows into the beamline chamber 1107 in the form of clustered andunclustered gas transported by the gas jet 1118 and in the form ofadditional unclustered gas that leaks through the gas skimmer aperture1120. A pressure sensor 1330 transmits pressure data from the beamlinechamber 1107 through an electrical cable 1332 to a pressure sensorcontroller 1334, which measures and displays pressure in the beamlinechamber 1107. The pressure in the beamline chamber 1107 depends on thebalance of gas flow into the beamline chamber 1107 and the pumping speedof the vacuum pump 1146 b. By selection of the diameter of the gasskimmer aperture 1120, the flow of source gas 1112 through the nozzle1110, and the pumping speed of the vacuum pump 1146 b, the pressure inthe beamline chamber 1107 equilibrates at a pressure, PB, determined bydesign and by nozzle flow. The beam flight path from grounded electrode1144 to workpiece holder 162, is for example, 100 cm. By design andadjustment PB may be approximately 6×10⁻⁵ torr (8×10⁻³ pascal). Thus theproduct of pressure and beam path length is approximately 6×10⁻³ torr-cm(0.8 pascal-cm) and the gas target thickness for the beam isapproximately 1.94×1014 gas molecules per cm2, which is observed to beeffective for dissociating the gas cluster ions in the GCIB 1128. VAccmay be for example 30 kV and the GCIB 1128 is accelerated by thatpotential. A pair of deflection plates (1302 and 1304) is disposed aboutthe axis 1154 of the GCIB 1128. A deflector power supply 1306 provides apositive deflection voltage VD to deflection plate 1302 via electricallead 1308. Deflection plate 1304 is connected to electrical ground byelectrical lead 1312 and through current sensor/display 1310. Deflectorpower supply 1306 is manually controllable. VD may be adjusted from zeroto a voltage sufficient to completely deflect the ionized portion 1316of the GCIB 1128 onto the deflection plate 1304 (for example a fewthousand volts). When the ionized portion 1316 of the GCIB 1128 isdeflected onto the deflection plate 1304, the resulting current, IDflows through electrical lead 1312 and current sensor/display 1310 forindication. When VD is zero, the GCIB 1128 is undeflected and travels tothe workpiece 1160 and the workpiece holder 1162. The GCIB beam currentIB is collected on the workpiece 1160 and the workpiece holder 1162 andflows through electrical lead 1168 and current sensor/display 1320 toelectrical ground. IB is indicated on the current sensor/display 1320. Abeam gate 1172 is controlled through a linkage 1338 by beam gatecontroller 1336. Beam gate controller 1336 may be manual or may beelectrically or mechanically timed by a preset value to open the beamgate 1172 for a predetermined interval. In use, VD is set to zero, thebeam current, IB, striking the workpiece holder is measured. Based onprevious experience for a given GCIB process recipe, an initialirradiation time for a given process is determined based on the measuredcurrent, IB. VD is increased until all measured beam current istransferred from IB to ID and ID no longer increases with increasing VD.At this point a Neutral Beam 1314 comprising energetic dissociatedcomponents of the initial GCIB 1128 irradiates the workpiece holder1162. The beam gate 1172 is then closed and the workpiece 1160 placedonto the workpiece holder 1162 by conventional workpiece loading means(not shown). The beam gate 1172 is opened for the predetermined initialradiation time. After the irradiation interval, the workpiece may beexamined and the processing time adjusted as necessary to calibrate theduration of Neutral Beam processing based on the measured GCIB beamcurrent IB. Following such a calibration process, additional workpiecesmay be processed using the calibrated exposure duration.

The Neutral Beam 1314 contains a repeatable fraction of the initialenergy of the accelerated GCIB 1128. The remaining ionized portion 1316of the original GCIB 1128 has been removed from the Neutral Beam 1314and is collected by the grounded deflection plate 1304. The ionizedportion 1316 that is removed from the Neutral Beam 1314 may includemonomer ions and gas cluster ions including intermediate size gascluster ions. Because of the monomer evaporation mechanisms due tocluster heating during the ionization process, intra-beam collisions,background gas collisions, and other causes (all of which result inerosion of clusters) the Neutral Beam substantially consists of neutralmonomers, while the separated charged particles are predominatelycluster ions. The inventors have confirmed this by suitable measurementsthat include re-ionizing the Neutral Beam and measuring the charge tomass ratio of the resulting ions. As will be shown below, certainsuperior process results are obtained by processing workpieces usingthis Neutral Beam.

FIG. 10 is a schematic of a Neutral Beam processing apparatus 1400 asmay, for example, be used in generating Neutral Beams as may be employedin embodiments of the invention. It uses a thermal sensor for NeutralBeam measurement. A thermal sensor 1402 attaches via low thermalconductivity attachment 1404 to a rotating support arm 1410 attached toa pivot 1412. Actuator 1408 moves thermal sensor 1402 via a reversiblerotary motion 1416 between positions that intercept the Neutral Beam1314 or GCIB 1128 and a parked position indicated by 1414 where thethermal sensor 1402 does not intercept any beam. When thermal sensor1402 is in the parked position (indicated by 1414) the GCIB 1128 orNeutral Beam 1314 continues along path 1406 for irradiation of theworkpiece 1160 and/or workpiece holder 1162. A thermal sensor controller1420 controls positioning of the thermal sensor 1402 and performsprocessing of the signal generated by thermal sensor 1402. Thermalsensor 1402 communicates with the thermal sensor controller 1420 throughan electrical cable 1418. Thermal sensor controller 1420 communicateswith a dosimetry controller 1432 through an electrical cable 1428. Abeam current measurement device 1424 measures beam current IB flowing inelectrical lead 1168 when the GCIB 1128 strikes the workpiece 1160and/or the workpiece holder 1162. Beam current measurement device 1424communicates a beam current measurement signal to dosimetry controller1432 via electrical cable 1426. Dosimetry controller 1432 controlssetting of open and closed states for beam gate 1172 by control signalstransmitted via linkage 1434. Dosimetry controller 1432 controlsdeflector power supply 1440 via electrical cable 1442 and can controlthe deflection voltage VD between voltages of zero and a positivevoltage adequate to completely deflect the ionized portion 1316 of theGCIB 1128 to the deflection plate 1304. When the ionized portion 1316 ofthe GCIB 1128 strikes deflection plate 1304, the resulting current ID ismeasured by current sensor 1422 and communicated to the dosimetrycontroller 1432 via electrical cable 1430. In operation dosimetrycontroller 1432 sets the thermal sensor 1402 to the parked position1414, opens beam gate 1172, sets VD to zero so that the full GCIB 1128strikes the workpiece holder 1162 and/or workpiece 1160. The dosimetrycontroller 1432 records the beam current IB transmitted from beamcurrent measurement device 1424. The dosimetry controller 1432 thenmoves the thermal sensor 1402 from the parked position 1414 to interceptthe GCIB 1128 by commands relayed through thermal sensor controller1420. Thermal sensor controller 1420 measures the beam energy flux ofGCIB 1128 by calculation based on the heat capacity of the sensor andmeasured rate of temperature rise of the thermal sensor 1402 as itstemperature rises through a predetermined measurement temperature (forexample 70 degrees C.) and communicates the calculated beam energy fluxto the dosimetry controller 1432 which then calculates a calibration ofthe beam energy flux as measured by the thermal sensor 1402 and thecorresponding beam current measured by the beam current measurementdevice 1424. The dosimetry controller 1432 then parks the thermal sensor1402 at parked position 1414, allowing it to cool and commandsapplication of positive VD to deflection plate 1302 until all of thecurrent ID due to the ionized portion of the GCIB 1128 is transferred tothe deflection plate 1304. The current sensor 1422 measures thecorresponding ID and communicates it to the dosimetry controller 1432.The dosimetry controller also moves the thermal sensor 1402 from parkedposition 1414 to intercept the Neutral Beam 1314 by commands relayedthrough thermal sensor controller 420. Thermal sensor controller 420measures the beam energy flux of the Neutral Beam 1314 using thepreviously determined calibration factor and the rate of temperaturerise of the thermal sensor 1402 as its temperature rises through thepredetermined measurement temperature and communicates the Neutral Beamenergy flux to the dosimetry controller 1432. The dosimetry controller1432 calculates a neutral beam fraction, which is the ratio of thethermal measurement of the Neutral Beam 1314 energy flux to the thermalmeasurement of the full GCIB 1128 energy flux at sensor 1402. Undertypical operation, a neutral beam fraction of from about 5% to about 95%is achieved. Before beginning processing, the dosimetry controller 1432also measures the current, ID, and determines a current ratio betweenthe initial values of IB and ID. During processing, the instantaneous IDmeasurement multiplied by the initial IB/ID ratio may be used as a proxyfor continuous measurement of the IB and employed for dosimetry duringcontrol of processing by the dosimetry controller 1432. Thus thedosimetry controller 1432 can compensate any beam fluctuation duringworkpiece processing, just as if an actual beam current measurement forthe full GCIB 1128 were available. The dosimetry controller uses theneutral beam fraction to compute a desired processing time for aparticular beam process. During the process, the processing time can beadjusted based on the calibrated measurement of ID for correction of anybeam fluctuation during the process.

As the atomic force microscope (AFM) images shown in FIGS. 3 and 4demonstrate, it is possible to dramatically affect the medical devicesurface utilizing gas cluster ion beam processing. FIG. 3 shows a stentsurface before GCIB treatment with gross surface micro-roughness on astrut edge. The surface roughness measured an Ra of 113 angstroms and anRRMS of 148 angstroms. These irregularities highlight the surfacecondition at the cellular level where thrombosis begins. FIG. 4 showsthe stent surface after GCIB processing where the surfacemicro-roughness has been eliminated without any measurable physical orstructural change to the integrity of the stent itself. The post-GCIBsurface roughness measured an Ra of 19 angstroms and an RRMS of 25angstroms. In this manner, GCIB processing also provides the addedbenefit of smoothing the surface of the medical device. Non-smoothsurfaces may snare fibrinogen, platelets, and other matter furtherpromoting stenosis.

With reference to FIG. 5, a drug delivery system 10, which includes adrug-containing medium 12 and an optional substrate or medical device14, is shown prior to processing by the method of the present invention.Medical device 14 is only representational and may take any suitableform. Device 14 may include an implantable medical device such as astent or any other medical device, which may benefit from an in situdrug delivery mechanism. Optionally, the use of substrate or device 14may be limited to the fabrication of drug containing medium 12, whereinsubstrate or device 14 is removed from medium 12 prior to implantation.Substrate or device 14 maybe he constructed of any suitable materialsuch as, for example, metal, ceramic or a polymer. Portions of substrateor device 14 may also be surface treated using GCIB in accordance withthe method mentioned above, prior to the application of drug/polymermedium 12.

Drug containing medium 12 may take any suitable form such as the variouspolymer arrangements discussed above. Medium 12 may include just asingle layer of drug containing material, or it may include multiplelayers 16, 18, 20, as described above. Although the existing artidentifies the use of an outer layer to control initial drug release,the process of the present invention may be used with this knownarrangement to further control surface characteristics of the medium,including the drug release rate after initial in situ liquid exposure.Drug medium 12 may be applied to device 14 in any suitable arrangementfrom just a portion to complete or almost complete enclosure of device14.

One method of application of medium 12 to device 14 uses a drug polymermixture with a volatile solvent, which is deposited upon a surface ofdevice 14. The solvent is evaporated to leave a cohesive drug/polymermixture in the form of medium 12, attached to the substrate. Once thesolvent is evaporated, drug medium 12 may form a cohesive mixture ormass and thereby provide a suitable drug delivery system, even in theabsence of device 14.

With reference to FIG. 6, the drug delivery system 10 is shownundergoing irradiation with a gas cluster ion beam. A stream 30 of gascluster molecules is being scanned across the cross section of drugdelivery device 10. The clusters 32 break up upon impact with thesurface 34 resulting in the shallow implantation of individual or smallgroups of molecules 36. Most of the individual molecules 36 stop withinthe first couple of molecular levels of medium 12 with the result thatmost of a thin layer 38 at surface 34 is densified or carbonized by theimpinging molecules. The sealing of surface 34 is not complete, asvarious openings 39 remain in surface 34 which openings allow for theelution of drugs from medium 12. Thus, it is through the amount of GCIBirradiation that the characteristics of surface 34 are determined. Thegreater the amount of irradiation, the fewer and smaller are theopenings in surface 34, thereby slowing the release of drugs from medium12. Also, this densification or carbonization of surface 34 causespacification or sealing of surface 34, which can decrease thebio-reactivity of surface 34 in contact with living tissue. In the caseof some polymer materials which may be used for medium 12, thedensification or carbonization can limit the release of volatile organiccompounds by the medium 12 into surrounding living tissue. Thus, theprocess of the present invention enhances the choices of materials whichmay be used to construct medium 12 and can reduce risk factorsassociated with those material choices.

FIGS. 11A through 11D show the comparative effects of full and chargeseparated beams on a gold thin film. In an experimental setup, a goldfilm deposited on a silicon substrate was processed by a full GCIB(charged and neutral components), a Neutral Beam (charged componentsdeflected out of the beam), and a deflected beam comprising only chargedcomponents. All three conditions are derived from the same initial GCIB,a 30 kV accelerated Ar GCIB. Gas target thickness for the beam pathafter acceleration was approximately 2×1014 argon gas atoms per cm2. Foreach of the three beams, exposures were matched to the total energycarried by the full beam (charged plus neutral) at an ion dose of 2×1015gas cluster ions per cm2. Energy flux rates of each beam were measuredusing a thermal sensor and process durations were adjusted to ensurethat each sample received the same total thermal energy dose equivalentto that of the full (charged plus neutral) GCIB dose.

FIG. 11A shows an atomic force microscope (AFM) 5 micron by 5 micronscan and statistical analysis of an as-deposited gold film sample thathad an average roughness, Ra, of approximately 2.22 nm. FIG. 11B showsan AFM scan of the gold surface processed with the full GCIB—averageroughness, Ra, has been reduced to approximately 1.76 nm. FIG. 11C showsan AFM scan of the surface processed using only charged components ofthe beam (after deflection from the neutral beam components)—averageroughness, Ra, has been increased to approximately 3.51 nm. FIG. 11Dshows an AFM scan of the surface processed using only the neutralcomponent of the beam (after charged components were deflected out ofthe Neutral Beam)—average roughness, Ra, is smoothed to approximately1.56 nm. The full GCIB processed sample (B) is smoother than the asdeposited film (A). The Neutral Beam processed sample (D) is smootherthan the full GCIB processed sample (B). The sample (C) processed withthe charged component of the beam is substantially rougher than theas-deposited film. The results support the conclusion that the neutralportions of the beam contribute to smoothing and the charged componentsof the beam contribute to roughening. Thus it is seen that acceleratedNeutral Beams derived from a GCIB provide superior smoothing even tothat of GCIB.

FIGS. 12A and 12B show comparative results of full GCIB and Neutral Beamprocessing of a drug film deposited on a cobalt-chrome coupon used toevaluate drug elution rate for a drug eluting coronary stent. FIG. 12Arepresents a sample irradiated using an argon GCIB (including thecharged and neutral components) accelerated using VAcc of 30 kV with anirradiated dose of 2×1015 gas cluster ions per cm2. FIG. 12B representsa sample irradiated using a Neutral Beam derived from an argon GCIBaccelerated using VAcc of 30 kV. The Neutral Beam was irradiated with athermal energy dose equivalent to that of a 30 kV accelerated, 2×1015gas cluster ion per cm2 dose (equivalent determined by beam thermalenergy flux sensor). The irradiation for both samples was performedthrough a cobalt chrome proximity mask having an array of circularapertures of approximately 50 microns diameter for allowing beamtransmission. FIG. 12A is a scanning electron micrograph of a 300 micronby 300 micron region of the sample that was irradiated through the maskwith full beam. FIG. 12B is a scanning electron micrograph of a 300micron by 300 micron region of the sample that was irradiated throughthe mask with a Neutral Beam. The sample shown in FIG. 12A exhibitsdamage and etching caused by the full beam where it passed through themask. The sample shown in FIG. 12B exhibits no visible effect. Inelution rate tests in physiological saline solution, the samplesprocessed like the Figure B sample (but without mask) exhibited superior(delayed) elution rate compared to the samples processed like the FIG.12A sample (but without mask). The results support the conclusion thatprocessing with the Neutral Beam contributes to the desired delayedelution effect, while processing with the full GCIB (charged plusneutral components) contributes to weight loss of the drug by etching,with inferior (less delayed) elution rate effect.

To further illustrate the ability of an accelerated Neutral Beam derivedfrom an accelerated GCIB to aid in attachment of a drug to a surface andto provide drug modification in such a way that it results in delayeddrug elution, an additional test was performed. Silicon couponsapproximately 1 cm by 1 cm (1 cm2) were prepared from highly polishedclean semiconductor-quality silicon wafers for use as drug depositionsubstrates. A solution of the drug Rapamycin (Catalog number R-5000, LCLaboratories, Woburn, Mass. 01801, USA) was formed by dissolving 500 mgof Rapamycin in 20 ml of acetone. A pipette was then used to dispenseapproximately 5 micro-liter droplets of the drug solution onto eachcoupon. Following atmospheric evaporation and vacuum drying of thesolution, this left approximately 5 mm diameter circular Rapamycindeposits on each of the silicon coupons. Coupons were divided intogroups and either left un-irradiated (controls) or irradiated withvarious conditions of Neutral Beam irradiation. The groups were thenplaced in individual baths (bath per coupon) of human plasma for 4.5hours to allow elution of the drug into the plasma. After 4.5 hours, thecoupons were removed from the plasma baths, rinsed in deionized waterand vacuum dried. Weight measurements were made at the following stagesin the process: 1) pre-deposition clean silicon coupon weight; 2)following deposition and drying, weight of coupon plus deposited drug;3) post-irradiation weight; and 4) post plasma-elution and vacuum dryingweight. Thus for each coupon the following information is available: 1)initial weight of the deposited drug load on each coupon; 2) the weightof drug lost during irradiation of each coupon; and 3) the weight ofdrug lost during plasma elution for each coupon. For each irradiatedcoupon it was confirmed that drug loss during irradiation wasnegligible. Drug loss during elution in human plasma is shown inTable 1. The groups were as follows: Control Group—no irradiation wasperformed; Group 1—irradiated with a Neutral Beam derived from a GCIBaccelerated with a VAcc of 30 kV. The Group 1 irradiated beam energydose was equivalent to that of a 30 kV accelerated, 5×10¹⁴ gas clusterion per cm2 dose (energy equivalence determined by beam thermal energyflux sensor); Group 2—irradiated with a Neutral Beam derived from a GCIBaccelerated with a VAcc of 30 kV. The Group 2 irradiated beam energydose was equivalent to that of a 30 kV accelerated, 1×1014 gas clusterion per cm2 dose (energy equivalence determined by beam thermal energyflux sensor); and Group 3—irradiated with a Neutral Beam derived from aGCIB accelerated with a VAcc of 25 kV. The Group 3 irradiated beamenergy dose was equivalent to that of a 25 kV accelerated, 5×1014 gascluster ion per cm2 dose (energy equivalence determined by beam thermalenergy flux sensor).

TABLE 1 Group Group 1 Group 2 Group 3 [Dose] [5 × 10¹⁴] [1 × 10¹⁴] [5 ×10¹⁴] {V_(Acc)} Control {30 kV} {30 kV} {25 kV} Start Elution StartElution Start Elution Start Elution Load Loss Elution Load Loss ElutionLoad Loss Load Loss Elution Coupon # (μg) (μg) Loss % (μg) (μg) Loss %(μg) (μg) Loss % (μg) (μg) Loss % 1 83 60 72 88 4 5 93 10 11 88 — 0 2 8755 63 100 7 7 102 16 16 82 5 6 3 88 61 69 83 2 2 81 35 43 93 1 1 4 96 7275 — — — 93 7 8 84 3 4 Mean 89 62 70 90 4 5 92 17 19 87 2 3 σ 5 7 9 3 913 5 2 p value 0.00048 0.014 0.00003

Table 1 shows that for every case of Neutral Beam irradiation (Groups 1through 3), the drug lost during a 4.5-hour elution into human plasmawas much lower than for the un-irradiated Control Group. This indicatesthat the Neutral Beam irradiation results in better drug adhesion and/orreduced elution rate as compared to the un-irradiated drug. The p values(heterogeneous unpaired T-test) indicate that for each of the NeutralBeam irradiated Groups 1 through 3, relative to the Control Group, thedifference in the drug retention following elution in human plasma wasstatistically significant.

FIG. 13A shows a sectional view 300A of a prior art hole 102 in priorart stent 100, illustrating a prior art method of loading a hole with adrug by employing polymers. A therapeutic layer 304 consists of a drugor a drug-polymer mixture. A barrier layer 302 on the inner surface 108of the stent 100 comprises a polymer and prevents elution or controlsthe elution rate of the therapeutic layer 304 to the inner portion(lumen) of the stent. A second barrier layer 306 on the outer surface106 of the stent 100 comprises a polymer and controls the elution rateof the therapeutic layer 304 to the outer portion (vascular scaffold) ofthe stent. The barrier layers 302 and 306 may also control or preventthe diffusion of water or other biological fluids from outside of thestent into the therapeutic layer 304 retained by the hole in the stent.The barrier layers 302 and 306 may be biodegradable or erodiblematerials comprising polymer to provide a delayed release of theenclosed therapeutic layer 304. The therapeutic layer 304 may be a drugor alternatively may be a mixture of drug and polymer to further delayor control the elution or release rate of the therapeutic layer 304.

FIG. 13B shows a sectional view 300B of a prior art hole 102 in priorart stent 100, illustrating a prior art method of loading a hole withmultiple layers of a drug by employing polymers. Therapeutic layers 308,312 consist respectively of a drug or a drug-polymer mixture and maycomprise similar or dissimilar drugs. Barrier layer 302 on the innersurface 108 of the stent 100 comprises a polymer and prevents elution orcontrols the elution rate of the therapeutic layer 308 to the innerportion (lumen) of the stent. A second barrier layer 314 on the outersurface 106 of the stent 100 comprises a polymer and controls theelution rate of the therapeutic layer 312 to the outer portion (vascularscaffold) of the stent. A third barrier layer 310 may comprise polymerand separates the therapeutic layers 308 and 312 and may also preventthe elution or control the elution rate of the therapeutic layers 308and 310. The barrier layers 302, 310 and 314 may also control or preventthe diffusion of water or other biological fluids from outside of thestent into the therapeutic layers 308 and 312 retained by the hole inthe stent. The barrier layers 302, 310, and 314 may be biodegradable orerodible materials comprising polymer to provide a delayed release ofthe enclosed therapeutic layers 308 and 312. The therapeutic layers 308and 312 may be each be either a drug or alternatively may be a mixtureof drug and polymer to further delay or control the elution or releaserate of the therapeutic layers 308 and 312.

FIG. 13C shows a sectional view 300C of a prior art blind-hole 202 in aprior art stent 200, illustrating a prior art method of loading a holewith a drug by employing polymers. A therapeutic layer 350 consists of adrug or a drug-polymer mixture. A barrier layer 352 on the outer surface206 of the stent 200 comprises a polymer and controls the elution rateof the therapeutic layer 350 to the outer portion (vascular scaffold) ofthe stent. The barrier layer 352 may also control or prevent thediffusion of water or other biological fluids from outside of the stentinto the therapeutic layer 350 retained by the hole in the stent. Thebarrier layer 352 may be biodegradable or erodible material comprisingpolymer to provide a delayed release of the enclosed therapeutic layer350. The therapeutic layer 350 may be a drug or alternatively may be amixture of drug and polymer to further delay or control the elution orrelease rate of the therapeutic material.

FIG. 14A shows sectional view 400A of a strut of a stent illustrating astep in the formation of a drug-loaded through-hole in a stent 100according to an embodiment of the invention. A stent 100 has athrough-hole 102. The stent has an inner surface 108 forming the lumenof the stent and has an outer surface 106 forming the vascular scaffoldportion of the stent. As a step in the embodiment of the invention, abarrier layer 402 is deposited on the inner surface 108 of the stent 100according to known technology. The barrier layer 402 may consist ofpolymer or of other biocompatible barrier material.

FIG. 14B shows sectional view 400B of a strut of a stent illustrating astep in the formation of a drug-loaded through-hole in a stent 100following the step shown in FIG. 14A. In the step shown in FIG. 14B, adrug 410 is deposited in the hole 102 in the stent 100. The depositionof the drug 410 may be by any of numerous methods, including spraying,dipping, electrostatic deposition, ultrasonic spraying, vapordeposition, or preferably by discrete droplet-on-demand fluid jettingtechnology. When spraying, dipping, electrostatic deposition, ultrasonicspraying, vapor deposition, or similar techniques are employed, aconventional masking scheme can be beneficially employed to limitdeposition to the hole or to several or all of the holes in a stent.Discrete droplet-on-demand fluid-jetting is a preferred depositionmethod because it provides the ability to introduce precise volumes ofliquid drugs or drugs-in-solution into precisely programmable locations.Discrete droplet-on-demand fluid jetting may be accomplished usingcommercially available fluid-jet print head jetting devices as areavailable (for example, not limitation) from MicroFab Technologies,Inc., of Plano, Tex. When the drug 410 is a liquid or adrug-in-solution, it is preferably dried or otherwise hardened beforeproceeding to the next step. The drying or hardening step may includebaking, low temperature baking, or vacuum evaporation, as examples.

FIG. 14C shows sectional view 400C of a strut of a stent illustrating astep in the formation of a drug-loaded through-hole in a stent 100following the step shown in FIG. 14B. In the step shown in FIG. 14C, thedrug 410 deposited in the hole 102 in the stent 100 is irradiated by abeam 408, preferably a GCIB or an accelerated Neutral Beam, to form athin barrier layer 412 by modification of a thin upper region of thedrug 410. The thin barrier layer 412 consists of drug 410 modified todensify, carbonize or partially carbonize, denature, cross-link, orpolymerize molecules of the drug in the thin uppermost layer of the drug410. The thin barrier layer 412 may have a thickness on the order ofabout 10 nanometers or even less. In modifying the surface a beam 408comprising preferably argon or another inert gas in the form ofaccelerated cluster ions, accelerated neutral clusters, or acceleratedneutral monomers is employed. The beam 408 is preferably acceleratedwith an accelerating potential of from 5 kV to 50 kV or more. Thecoating layer is preferably exposed to a GCIB dose of at least about1×10¹³ gas cluster ions per square centimeter (or in the case of NeutralBeam, a dose that has the energy equivalent determined by thermal beamenergy flux sensor). By selecting the dose and/or accelerating potentialof the beam 408, the characteristics of the thin barrier layer 412 maybe adjusted to permit control of the release or elution rate and/or therate of inward diffusion of water and/or other biological fluids whenthe stent 100 is implanted and expanded. In general, increasingacceleration potential increases the thickness of the thin barrier layerthat is formed, and modifying the GCIB or Neutral Beam dose changes thenature of the thin barrier layer by changing the degree of crosslinking, densification, carbonization, denaturization, and/orpolymerization that results. This provides means to control the rate atwhich drug will subsequently release or elute through the barrier and/orthe rate at which water and/or biological fluids my diffuse into thedrug from outside.

FIG. 14D shows sectional view 400D of a strut of a stent illustrating adrug-loaded through-hole in a stent 100 following the step shown in FIG.14C. In FIG. 14D, the steps of depositing a drug and using GCIB oraccelerated Neutral Beam irradiation to form a thin barrier layer in thesurface of the drug has been repeated (for example) twice more beyondthe stage shown in FIG. 14C. FIG. 14D shows the additional layers ofdrugs (414 and 418) and the additional beam-formed thin barrier layers416 and 420. The drugs 410, 414, and 418 may be the same drug materialor may be different drugs with different therapeutic modes. Thethicknesses of the layers of drugs 410, 414, and 418 are shown to bedifferent, indicating that different drug doses may be deposited in eachindividual layer. Alternatively, the thicknesses (and doses) may be thesame in some or all layers. The properties of each of the thin barrierlayers 412, 416, and 420 may also be individually adjusted by selectingGCIB or accelerated Neutral Beam properties at each barrier layerformation irradiation step by controlling the GCIB or acceleratedNeutral Beam properties as discussed above. Although FIG. 14D shows ahole loaded with three layers of drugs, there is complete freedom withinthe constraints of the hole depth and drug deposition capabilities toutilize from one to a very large number of layers all within the spiritof the invention. The very thin barrier layers that can be formed byGCIB or accelerated Neutral Beam processing and the ability to depositvery small volumes of drug by, for example, discrete droplet-on-demandfluid-jetting technology, make many tens or even hundreds of layerspossible. Each drug layer may be different or similar drug materials,may be mixtures of compatible drugs, may be larger or smaller volumes,etcetera, providing great flexibility and control in the therapeuticeffect of the drug delivery system and in tailoring the sequencing andelution rates of one or more drugs.

The drug delivery system shown in FIG. 14D is an improvement over priorart systems, but it suffers from the fact that it utilizes aconventional barrier layer 402, that may consist of polymer or of otherbiocompatible barrier material. In the case of a stent, for example, itis generally not convenient to form a barrier layer by beam processingin the interior (lumen) surface of an unexpanded stent. Thusconventional barrier layer 402 is generally required. Use of polymersmay be avoided by employing other biocompatible materials for formationof the barrier layer 402; however even so, there is risk of subsequentflaking of the material resulting in its undesired release in situ.FIGS. 5A, 5B, and 5C show another embodiment of the present inventionthat avoids the undesirable need to use conventional barrier materials.

FIG. 15A shows sectional view 500A of a strut of a stent illustrating astep in the formation of a drug-loaded blind-hole in a stent 200according to an embodiment of the invention. A stent 200 has ablind-hole 202. The stent has an inner surface 208 forming the lumen ofthe stent and has an outer surface 206 forming the vascular scaffoldportion of the stent. As a step in the embodiment of the invention, adrug 502 is deposited in the hole 202 in the stent 200. Not shown, andoptionally, a GCIB or accelerated Neutral Beam cleaning process may beemployed to clean the surfaces of the hole 202 prior to depositing drug502 in the hole 202. The deposition of the drug 502 may be by any of theabove-discussed methods. Discrete droplet-on-demand fluid jetting is apreferred deposition method because it provides the ability to introduceprecise volumes of liquid drugs or drugs-in-solution into preciselyprogrammable locations. When the drug 502 is a liquid or adrug-in-solution, it is preferably dried or otherwise hardened beforeproceeding to the next step. The drying or hardening may include baking,low temperature baking, or vacuum evaporation, as examples.

FIG. 15B shows sectional view 500B of a strut of a stent illustrating astep in the formation of a drug-loaded blind-hole in a stent 200following the step shown in FIG. 15A. In the step shown in FIG. 15B, thedrug 502 deposited in the hole 202 in the stent 200 is irradiated by abeam 504, preferably a GCIB or an accelerated Neutral Beam to form athin barrier layer 506 by modification of a thin upper region of thedrug 502. The thin barrier layer 506 consists of drug 502 modified todensify, carbonize or partially carbonize, denature, cross-link, orpolymerize molecules of the drug in the thin uppermost layer of the drug502. The thin barrier layer 506 may have a thickness on the order ofabout 10 nanometers or even less. In modifying the surface, a beam 504comprising preferably argon or another inert gas in the form ofaccelerated cluster ions accelerated neutral clusters, or acceleratedneutral monomers is employed. The beam 504 is preferably acceleratedwith an accelerating potential of from 5 kV to 50 kV or more. Thecoating layer is preferably exposed to a GCIB dose of at least about1×10¹³ gas cluster ions per square centimeter (or in the case of aNeutral Beam, a dose that has the energy equivalent determined by athermal beam energy flux sensor). By selecting the dose and/oraccelerating potential of the beam 504, the characteristics of the thinbarrier layer 506 may be adjusted to permit control of the elution rateand/or the rate of inward diffusion of water and/or other biologicalfluids when the stent 200 is implanted and expanded. In general,increasing acceleration potential increases the thickness of the thinbarrier layer that is formed, and modifying the GCIB or acceleratedNeutral Beam dose changes the nature of the thin barrier layer bychanging the degree of cross linking, densification, carbonization,denaturization, and/or polymerization that results. This provides meansto control the rate at which drug will subsequently release or elutethrough the barrier and/or the rate at which water and/or biologicalfluids my diffuse into the drug from outside.

FIG. 15C shows sectional view 500C of a drug-loaded blind-hole in astent 200 having multiple drug layers, according to an embodiment of theinvention. The steps of depositing a drug and using ion beam irradiationto form a thin barrier layer in the surface of the drug has been asdescribed above for FIGS. 5A and 5B have been applied (for example)three times in succession, forming a blind-hole 202 loaded with threedrugs 510, 514, and 518, each having a thin barrier layer 512, 516, and520 having been formed by irradiation, preferably GCIB or acceleratedNeutral Beam, irradiation. The drugs 510, 514, and 518 may be the samedrug material or may be different drugs with different therapeuticmodes. The thicknesses of the layers of drugs 510, 514, and 518 areshown to be different, indicating that different drug doses may bedeposited in each individual layer. Alternatively, the thicknesses (anddoses) may be the same in some or all layers. The properties of each ofthe thin barrier layers 512, 516, and 520 may also be individuallyadjusted by controlling beam properties at each barrier layer formationirradiation step by controlling the GCIB or accelerated Neutral Beamproperties as discussed above. Although three layers of drugs are shown,there is complete freedom within the constraints of the hole depth anddrug deposition capabilities to utilize from one to a very large numberof layers all within the spirit of the invention.

FIG. 16A shows a cross section view 600A of a portion of a blind-hole inan implantable medical device (a stent 200, for example), wherein thehole 202 has been formed by laser machining and has a resulting sharp or(as shown) burred edge 602 resulting from the machining process. In mostcases such an edge or burr is undesirable in an implantable medicaldevice. GCIB or accelerated Neutral Beam processing can beadvantageously employed to remove such burr or sharp edge prior toloading the hole with a drug and forming a thin barrier layer (asdescribed above).

FIG. 16B shows a cross section view 600B of the hole 202 in stent 200processed by irradiation with a beam 604, preferably a GCIB or anaccelerated Neutral Beam, to remove the sharp or burred edge 602 by GCIBor accelerated Neutral Beam processing, forming a smooth edge 606. Abeam 604 comprising preferably argon, another inert gas, oxygen, ornitrogen in the form of accelerated cluster ions, accelerated neutralions, or accelerated neutral monomers is employed. The beam 604 ispreferably accelerated with an accelerating potential of from 5 kV to 50kV or more. The coating layer is preferably exposed to a GCIB dose offrom about 1×10¹⁵ to about 1×10¹⁷ gas cluster ions per square centimeter(or in the case of Neutral Beam, a dose that has the energy equivalentdetermined by thermal beam energy flux sensor). By selecting the doseand/or accelerating potential of the GCIB 604, the etchingcharacteristics of the GCIB 604 are adjusted to control the amount ofetching and smoothing performed in forming smoothed edge 606. Ingeneral, increasing acceleration potential and or increasing the GCIB oraccelerated Neutral Beam dose increases the etching rate.

FIG. 17 shows a cross sectional view 700 of the surface 704 of a portion702 of a non-polymer implantable medical device having a variety ofdrug-loaded holes 706, 708, 710, 712, and 714 pointing out the diversityand flexibility of the invention. The implantable medical device could,for example, be any of a vascular stent, an artificial joint prosthesis,a cardiac pacemaker, or any other implantable non-polymer medical deviceand need not necessarily be a thin-walled device like a vascular orcoronary stent. The holes all have thin barrier layers 740 formedaccording to the invention on one or more layers of drug in each hole.For simplicity, not all of the thin barrier layers in FIG. 17 arelabeled with reference numerals, but hole 714 is shown containing afirst drug 736 covered with a thin barrier layer 740 (only thin barrierlayer 740 in hole 714 is labeled with a reference numeral, but eachcross-hatched region in FIG. 17 indicates a thin barrier layer, and allwill hereinafter be referred to by the exemplary reference numeral 740).Hole 706 contains a second drug 716 covered with a thin barrier layer740. Hole 708 contains a third drug 720 covered with a thin barrierlayer 740. Hole 710 contains a fourth drug 738 covered with a thinbarrier layer 740. Hole 712 contains fifth, sixth, and seventh drugs728, 726, and 724, each respectively covered with a thin barrier layer740. Each of the respective drugs 716, 720, 724, 726, 728, 736, and 738may be selected to be a different drug material or may be the same drugmaterials in various combinations of different or same. Each of the thinbarrier layers 740 may have the same or different properties forcontrolling elution or release rate and/or for controlling the rate ofinward diffusion of water or other biological fluids according to beam(preferably GCIB or accelerated Neutral Beam) processing principlesdiscussed herein above. Holes 706 and 708 have the same widths and filldepth 718, and thus hold the same volume of drugs, but the drugs 716 and720 may be different drugs for different therapeutic modes. The thinbarrier layers 740 corresponding respectively to holes 706 and 708 mayhave either same or differing properties for providing same or differentelution, release, or inward diffusion rates for the drugs contained inholes 706 and 708. Holes 708 and 710 have the same widths, but differingfill depths, 718 and 722 respectively, thus containing differing drugloads corresponding to differing doses. The thin barrier layers 740corresponding respectively to holes 708 and 710 may have either same ordiffering properties for providing same or different elution, release,or inward diffusion rates for the drugs contained in holes 708 and 710.Holes 710 and 712 have the same widths 730, and have the same filldepths 722, thus containing the same total drug loads, but hole 710 isfilled with a single layer of drug 738, while hole 712 is filled withmultiple layers of drug 724, 726, and 728, which may each be the same ordifferent volumes of drug representing the same or different doses andfurthermore may each be different drug materials for differenttherapeutic modes. Each of the thin barrier layers 740 for holes 710 and712 may have the same or different properties for providing same ordifferent elution, release, or inward diffusion rates for the drugscontained in the holes. Holes 708 and 714 have the same fill depths 718,but have different widths and thus contain different volumes and dosesof drugs 720 and 736. The thin barrier layers 740 correspondingrespectively to holes 708 and 714 may have either same or differingproperties for providing same or different elution, release, or inwarddiffusion rates for the drugs contained in holes 708 and 714. Theoverall hole pattern on the surface 704 of the implantable medicaldevice and the spacing between holes 732 may additionally be selected tocontrol the spatial distribution of drug dose across the surface of theimplantable medical device. Thus there are many flexible options in theapplication of the invention for controlling the types and doses anddose spatial distributions and temporal release sequences and releaserates and release rate temporal profiles of drugs delivered by the drugdelivery system of the invention.

FIG. 18A shows partial sectional schematic view 900A of a substrateillustrating a step in the formation of a drug-loaded substrate 801(which may for example be a surface on a stent or other implantablemedical device) according to an embodiment of the invention. A substrate801 has a surface 802. As a step in the embodiment of the invention, adrug 902 is deposited on the surface 802 of the substrate 801. Notshown, and optionally, a GCIB or accelerated Neutral Beam cleaningprocess may be employed to clean the surface 802 of the substrate 801prior to depositing drug 902 on the surface 802. The deposition of thedrug 902 may be by any of the above-discussed methods. Discretedroplet-on-demand fluid jetting is a preferred deposition method becauseit provides the ability to introduce precise volumes of liquid drugs ordrugs-in-solution into precisely programmable locations. When the drug902 is a liquid or a drug-in-solution, it is preferably dried orotherwise hardened before proceeding to the next step. The drying orhardening may include baking, low temperature baking, or vacuumevaporation, as examples.

FIG. 18B shows partial sectional schematic view 900B of a substrateillustrating a step in the formation of a drug-loaded substrate 801following the step shown in FIG. 18A. In the step shown in FIG. 18B, thedrug 902 deposited on the surface 802 of the substrate 801 is irradiatedby an accelerated Neutral Beam 904 to form a thin barrier layer 906 bymodification of a thin upper region of the drug 902. The thin barrierlayer 906 consists of drug 902 modified to densify, carbonize orpartially carbonize, denature, cross-link, or polymerize molecules ofthe drug in the thin uppermost layer of the drug 902 by the irradiationof the accelerated Neutral Beam 904. The thin barrier layer 906 may havea thickness on the order of about 10 nanometers or even less. Inmodifying the surface, an accelerated Neutral Beam 904 comprisingpreferably argon or another inert gas in the form of accelerated neutralclusters or accelerated neutral monomers is employed. The acceleratedNeutral Beam 904 is preferably accelerated with an acceleratingpotential of from 5 kV to 50 kV or more. The coating layer is preferablyexposed to a Neutral Beam dose that has the energy equivalent (as may bedetermined by a thermal beam energy flux sensor) of at least about1×10¹³ gas cluster ions per square centimeter at the accelerationvoltage VAcc employed. By selecting the dose and/or accelerating voltageof the accelerated Neutral Beam 904, the characteristics of the thinbarrier layer 906 may be adjusted to permit control of the elution rateand/or the rate of inward diffusion of water and/or other biologicalfluids when the substrate 801 is implanted. In general, increasingacceleration potential increases the thickness of the thin barrier layerthat is formed, and modifying the accelerated Neutral Beam dose changesthe nature of the thin barrier layer by changing the degree of crosslinking, densification, carbonization, denaturization, and/orpolymerization that results. These parameters provide means to controlthe rate at which drug will subsequently release or elute through thebarrier and/or the rate at which water and/or biological fluids mydiffuse into the drug from outside.

FIG. 18C shows partial sectional schematic view 900C of a drug-loadedsubstrate 801 having multiple drug layers and multiple barrier layers,according to an embodiment of the invention. The steps of depositing adrug and using beam irradiation to form a thin barrier layer in thesurface of the drug have been as described above for FIGS. 18A and 18Bhave been applied (for example) three times in succession, forming asurface 802 loaded with three drugs 910, 914, and 918, each having athin barrier layer 912, 916, and 920 having been formed by acceleratedNeutral Beam irradiation. The drugs 910, 914, and 918 may be the samedrug material or may be different drugs with different therapeuticmodes. The thicknesses of the layers of drugs 910, 914, and 918 areshown to be different, indicating the possibility that different drugdoses may be deposited in each individual layer. Alternatively, thethicknesses (and/or doses) may be the same in some or all layers. Theproperties of each of the thin barrier layers 912, 916, and 920 may alsobe individually adjusted by controlling beam properties at each barrierlayer formation irradiation step by controlling the accelerated NeutralBeam properties as discussed above. Although three layers of drugs areshown, there is complete freedom within the constraints of the drugdeposition capabilities to utilize from one to a very large number oflayers all within the spirit of the invention.

Studies have suggested that a wide variety of drugs may be useful at thesite of contact between the medical device and the in situ environment.For example, drugs such as anti-coagulants, anti-prolifics, antibiotics,immune-suppressing agents, vasodilators, anti-thrombotic substances,anti-platelet substances, and cholesterol reducing agents may reduceinstances of restenosis when diffused into the blood vessel wall afterinsertion of the stent. Although the present invention is described inreference to stents, its applications and the claims hereof are notlimited to stents and may include any contact with a living body wheredrug delivery may be helpful.

Although the benefits of employing the Neutral Beam for electricalcharging-free processing have been described with respect to variouselectrically insulating and/or high electrical resistivity materialssuch as insulating drug coatings, polymers, and other materials, it isunderstood by the inventors that all materials of poor or low electricalconductivity may benefit from using the Neutral Beam of the invention asa substitute for processing using techniques that transfer charges, likeion beams (including GCIB), plasmas, etc. It is intended that the scopeof the invention includes all such materials. It is further understoodby the inventors that Neutral Beam processing is often advantageous ascompared to GCIB and other ion beams, beyond the advantage of reducedsurface charging. Thus it is also valuable for processing even materialsthat are electrically conductive (such as, for example, metal stents orother metal medical devices or components), due to other the advantagesof Neutral Beam processing, especially of neutral monomer beamprocessing, which produces less surface damage, better smoothing, andsmoother interfaces between processed and underlying unprocessedregions, even in metals and highly conductive materials. It is intendedthat the scope of the invention include processing of such materials.

Although the benefits of employing Neutral Beam for modifying thesurfaces of drug materials on medical devices to control an elution rateof a drug in a fluid environment have been disclosed as an example, itis understood by the inventors that surfaces of other organic or evensome inorganic materials on other types of substrates may be modified tochange the rate at which they elute or release material in a fluidenvironment, or evaporate or sublimate or release material in an air orother gaseous environment or in a vacuum. It is intended that the scopeof the invention include processing of such materials using acceleratedNeutral Beams derived from accelerated GCIBs. Such materials may be inthe form of a coating on a substrate or in a bulk material form.

Although the invention has been described with respect to variousembodiments, it should be realized this invention is also capable of awide variety of further and other embodiments within the spirit andscope of the invention and the appended claims.

What is claimed is:
 1. A medical device having a surface adapted fordelivering one or more drugs, comprising: and one or more drug coatinglayers on the surface of the device, at least one of the drug coatinglayers having at least one barrier layer adapted for controlling a rateof flow of material across the at least one barrier layer, and furtherwherein the at least one barrier layer consists of drug modified byNeutral Beam irradiation.
 2. The medical device of claim 1, wherein theat least one barrier layer: controls a release rate of drugs; controlsan elution rate of drugs; or controls an inward diffusion rate of afluid into at least one of the one or more drug coating layers.
 3. Themedical device of claim 1, wherein at least one drug coating layer ofthe one or more drug coating layers contains a first quantity of a firstdrug, said first drug overlaid by a first barrier layer comprisingmodified first drug, said first barrier layer overlaid by a secondquantity of a second drug, said second drug overlaid by a second barrierlayer comprising modified second drug.
 4. The medical device of claim 3,wherein: the first drug and the second drug are the same drug ordifferent drugs; and the first barrier layer and the second barrierlayer are constructed to control a temporal release profile of the firstand second drugs.
 5. The medical device of claim 1, wherein thecontrolled flow rate is: a drug elution rate; a drug release rate; or afluid diffusion rate.
 6. The medical device of claim 1, wherein themedical device is any of: a vascular stent; a coronary stent; anartificial joint prosthesis; an artificial joint prosthesis component;or a coronary pacemaker.
 7. The medical device of claim 1, wherein theat least one barrier layer comprising modified drug is selected from thegroup consisting of: cross-linked drug molecules; a densified drug; acarbonized organic drug material; a polymerized drug; or a denaturizeddrug; and combinations thereof.
 8. The medical device of claim 1,wherein the at least one barrier layer comprises a biologically activematerial.
 9. A method of modifying a surface of a medical devicecomprising the steps: a. depositing a first drug coating layer on atleast a portion of the surface of the medical device; b. optionallydepositing one or more additional drug coating layers on the first drugcoating layer to form a plurality of drug coating layers; c. forming anaccelerated Neutral Beam; and d. irradiating a first exposed surface ofat least one of the first drug coating layer or any additional drugcoating layer with the Neutral Beam to form a barrier layer at the firstexposed surface.
 10. The method of claim 9, further comprising thesteps, prior to the depositing step a.: forming a second beam; andsecond irradiating at least a portion of the surface of the medicaldevice with the second beam to: clean the at least a portion of thesurface of the medical device; smooth the at least a portion of thesurface of the medical device; or remove a sharp or burred edge on theat least a portion of the surface of the medical device.
 11. The methodof claim 9, wherein the irradiating step d. forms the barrier layer bymodifying the drug at the exposed surface by: cross-linking molecules ofthe drug; densifying the drug; carbonizing the drug; polymerizing thedrug; or denaturing the drug.
 12. The method of claim 9, wherein thebarrier layer controls a rate of inward diffusion of a fluid into thedrug coating.
 13. The method of claim 9, wherein the barrier layercontrols a rate of outward elution of drug from the drug coating. 14.The method of claim 9, comprising the additional steps forming a thirdbeam and irradiating a second exposed surface of at least one of thefirst drug coating layer or any additional drug coating layer with thethird beam to form a second barrier layer at the second exposed surface.15. The method of claim 14, wherein the third beam is a Neutral Beam.16. The method of claim 14, wherein the third beam is a gas cluster ionbeam.
 17. The method of claim 14, wherein the first barrier layer andthe second barrier layer have different properties for differentlycontrolling elution rates of two drug coating layers.
 18. The method ofclaim 9 wherein the Neutral Beam is derived from an accelerated gascluster ion beam.
 19. The method of claim 9, wherein a first drugcoating layer and an additional drug coating layer comprise differentdrug materials.